tag:blogger.com,1999:blog-78734160178770822602024-03-15T18:10:24.854-07:00modern steroid scienceDriven by the great medicinal potential of the steroidal sex hormones and anti-inflammatory agents, the period of the 1930s through the 1950s has been called the golden age of steroid chemistry. In recent years, steroid research has witnessed a renaissance, as a new generation of scientists has begun to recognize the pharmacologically privileged nature of the steroidal molecular framework. This blog highlights achievements pertaining to steroid technologies published from 2010 to the present.BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.comBlogger103125tag:blogger.com,1999:blog-7873416017877082260.post-52051456541745609272016-12-21T08:16:00.000-08:002016-12-21T08:16:26.659-08:00The 2016 Modern Steroid Science 'Top Five'<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh68yrMQGS-zM5NlSZ8rgKDTbyhUHhOdMyB-bqz4fOkPKDBiU2yNHOHhe_7mNElg3qjgwBHdtUvbLOm4l0sVcTKc0RzRmiR0qLAfmmKByBs-e9EL3yBn2V3kmoRhJg_2S-7Gwe4YwxTZ06s/s1600/TOP5_rev.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh68yrMQGS-zM5NlSZ8rgKDTbyhUHhOdMyB-bqz4fOkPKDBiU2yNHOHhe_7mNElg3qjgwBHdtUvbLOm4l0sVcTKc0RzRmiR0qLAfmmKByBs-e9EL3yBn2V3kmoRhJg_2S-7Gwe4YwxTZ06s/s1600/TOP5_rev.png" /></a></div>
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<br />BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com12tag:blogger.com,1999:blog-7873416017877082260.post-69536510623567282622016-01-31T15:02:00.000-08:002016-01-31T18:00:50.613-08:00On the Existence of Human Pheromones<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjq_Sl_mFm5n6tkZh9kfSN55A3h8ZyVA1jhFbXQnK-jUeEyAbsFOCEe5Y9mmW-KE0Kfgeg-gr6uOr27d1FfOjW8ALbduFGxCjH3UMdvi5f-JKN3xRxjFs2Fe9GJllOWNRuT8YQuPt1nVs4I/s1600/brain_pig_structure.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="264" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjq_Sl_mFm5n6tkZh9kfSN55A3h8ZyVA1jhFbXQnK-jUeEyAbsFOCEe5Y9mmW-KE0Kfgeg-gr6uOr27d1FfOjW8ALbduFGxCjH3UMdvi5f-JKN3xRxjFs2Fe9GJllOWNRuT8YQuPt1nVs4I/s640/brain_pig_structure.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>A fictionalized version of Hank
Walter, the former chairman of International Flavors & Fragrances, Inc.
(IFF), is portrayed by actor Josh Charles on Season 2 of the Showtime series <i style="mso-bidi-font-style: normal;">Masters of Sex</i>. IFF was (and <a href="http://www.iff.com/" target="_blank"><span style="color: blue;">continues to be</span></a>) a massive global conglomerate that provided the chocolate
flavor in Cocoa Puffs, as well as scents for the foremost perfume makers of the
time. IFF and other private food and fragrance companies provided grant money
to Masters and Johnson’s clinic to develop a pheromonal perfume and this
collaboration served as a major plotline in Season 2 of the dramatic series. The
fictional Walter character, ‘Dan Logan,’ conducts research on the show (See
Figure above, left panel) aimed at marketing a natural aphrodisiac-infused
scent to the general public. This led me to wonder: What is the deal with human
pheromones? Have we actually identified smells (volatile molecules) that affect
human behavior or is this junk pseudoscience propagated by the perfume
industry? It turns out that the answer is: Yes, we have certainly identified olfactory signaling molecules that seem to influence our behavior. And the putative
pheromone structures are steroids.<o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span><a href="https://en.wikipedia.org/wiki/Pheromone" target="_blank"><span style="color: blue;">Pheromones</span></a> were first <a href="http://www.nature.com/nature/journal/v183/n4653/abs/183055a0.html" target="_blank"><span style="color: blue;">described</span></a> in
1959 as airborne chemosignal molecules that convey information and produce
behavioral, neuroendocrine or developmental changes in members of the same
species. Olfactory chemical communication is ubiquitous in the animal kingdom
but, until recently, was not believed to extend to <i>human</i> behavior and social
interaction. However, contemporary studies describing the gender-specific psychological
and physiological effects of two human steroids contradict this notion. The two
specific putative pheromones are <a href="https://en.wikipedia.org/wiki/Androstadienone" target="_blank"><span style="color: blue;">androsta-4,16-dien-3-one</span></a> and <a href="https://en.wikipedia.org/wiki/Estratetraenol" target="_blank"><span style="color: blue;">estratetraenol</span></a>
(structures displayed below), from the general steroid class referred to as 16-androstenes.
These are steroidal molecules that lack an oxygen atom at C17, which is
required for androgenic or estrogenic activity.</span></div>
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<span style="font-size: large;"> A <a href="http://www.cell.com/current-biology/abstract/S0960-9822(14)00327-3" target="_blank"><span style="color: blue;">2014 study</span></a> led by Wen Zhou at the
Chinese Academy of Sciences (Beijing) aimed to determine whether or not the
above-mentioned steroids communicate gender in a sex-specific manner. The
authors showed that smelling androstadienone biases heterosexual females, but
not males, toward perceiving images of walkers as more masculine. Moreover,
exposure to estratetraenol odor was found to bias heterosexual males toward perceiving the
walkers as more feminine. The results provide direct evidence that the two
steroids communicate opposite gender information with the larger implication of the work being that human visual gender perception draws on chemosensory biological
cues. Those chemosensory cues can be considered pheromones based on the
definition that is referenced above. The intriguing results reported by Zhou and co-workers are consistent with previous
findings that androstadienone increases cortisol levels and activates brain
areas linked to social cognition. In addition to documented effects on human
gender perception and physiology, there is also psychological evidence
regarding androstadienone’s direct impact on male behavior. In a <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062499" target="_blank"><span style="color: blue;">2013 investigation</span></a> conducted
in Finland, androstadienone was found to increase cooperative behavior in
decision-making tasks. Indeed, as a chemical signal of mate quality and
dominance, the steroid elicited observable psychological effects on male
subjects that seemed to place them in a socially subordinate position. Notably,
this was the first study to show that androstadienone directly influences behavior
in human males, acting in this instance as ‘the chemical equivalent of a
peacock’s tail.’</span></div>
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<o:p></o:p></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5pCoc7LUc-14PChk9oXrHvVkH1vPEFbNKT44b6GU5kr5AQGSJMeP5Xg3Eff1YdaETk7cNfxA_6a-cMqVQ0Y5UrRl_Uu-x6aRAbZM6VRIDJ6Qc-FT324Aeub_nKQ6Rr836SrselrbLeY1Z/s1600/biosynthesis.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="332" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5pCoc7LUc-14PChk9oXrHvVkH1vPEFbNKT44b6GU5kr5AQGSJMeP5Xg3Eff1YdaETk7cNfxA_6a-cMqVQ0Y5UrRl_Uu-x6aRAbZM6VRIDJ6Qc-FT324Aeub_nKQ6Rr836SrselrbLeY1Z/s640/biosynthesis.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The 16-androstenes that have been
identified in humans are biosynthesized from naturally occurring pregnenolone
(see Scheme above). The biogenesis of the putative steroidal pheromones
androstadienone and estratetraenol relies on the 16-ene-synthase activity of
cytochrome P450 17A1 (CYP17A1), which excises the side chain subtituent from the
enzymatic substrate and simultaneously installs the <span style="font-family: "symbol";">D</span><sup>16,17</sup> double bond within the steroidal D-ring.<o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>It’s interesting to compare the
structure of 5<span style="font-family: "symbol";">a-</span>androst-16-en-3-one to
the odorous macrocyclic ketone, <a href="https://en.wikipedia.org/wiki/Civetone" target="_blank"><span style="color: blue;">civetone</span></a>. Civetone is a known pheromone derived
from <a href="https://en.wikipedia.org/wiki/African_civet" target="_blank"><span style="color: blue;">African civet</span></a> musk that is used in perfumery. When drawn in a somewhat
biased fashion, key features of the two-dimensional structure of civetone are
cleanly superimposed over the corresponding groups found in the A and D-rings
of androstenone. The structural features responsible for a given odor have been
referred to as ‘olfactophores’ or ‘odotypes.’ <a href="https://en.wikipedia.org/wiki/Androstenone" target="_blank"><span style="color: blue;">Androstenone</span></a> happens to be the
active ingredient in a commercial product called <a href="http://www.kerbl.com/ftp/prod_documents/2290=22139=22156=PI_Boarmate_0312_EN_screen.pdf" target="_blank"><span style="color: blue;">Boarmate<sup>TM</sup></span></a>, which,
as one might gather from its name, was developed to assist farmers with swine
breeding.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqD9AHUjKPGncpHAtJ6t7PjDPwmEzA-naACdJQxM51qokWZ7fjhVIw45LmmRumFySzFb9kCNgqQ0rHsbi21KmUSVOqE9sJpEmqObtR1p6xNy_v3Yk9zC15jTXK2w5a4xjibEq3uZ_otCXd/s1600/civetone.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="324" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqD9AHUjKPGncpHAtJ6t7PjDPwmEzA-naACdJQxM51qokWZ7fjhVIw45LmmRumFySzFb9kCNgqQ0rHsbi21KmUSVOqE9sJpEmqObtR1p6xNy_v3Yk9zC15jTXK2w5a4xjibEq3uZ_otCXd/s640/civetone.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In vertebrates, odors are sensed by
members of a family of seven-transmembrane G-protein-coupled receptors called
odorant or <a href="https://en.wikipedia.org/wiki/Olfactory_receptor" target="_blank"><span style="color: blue;">olfactory receptors</span></a> (ORs) that are localized on the terminal knobs of
olfactory sensory neurons (see Diagram below). The human receptor <a href="https://en.wikipedia.org/wiki/OR7D4" target="_blank"><span style="color: blue;">OR7D4</span></a> responds specifically to
16-androstenes including androstadienone and androstenone. Upon odorant
binding, the OR undergoes a conformational change that activates an
olfactory-specific subtype of G-protein. This triggers a downstream signaling cascade
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be dependent on the OR7D4 gene variant that an individual carries. The OR7D4
genotype also <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035259" target="_blank"><span style="color: blue;">predicts</span></a> the sensory perception of meat containing androstenone,
which is consistent with the idea that genetic variation in this important OR
can alter food preferences. Whether one chooses to believe in the existence of human pheromones
or not, steroids clearly serve an essential olfactory signaling function that
impacts broadly ranging aspects of the human condition from gender perception to social
behavior to dietary choices. </span><o:p></o:p></div>
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BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com10tag:blogger.com,1999:blog-7873416017877082260.post-63815230046979711502016-01-17T11:45:00.000-08:002016-01-18T17:09:33.966-08:00Partial Synthesis of Linckosides A and B, Unique C8-Hydroxylated Steroids from the Okinawan Blue Starfish<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdWfEtPTTTxIfcmPXLS4a-rQ3dDI3mReNYt6_pzRpxRppVLGgYTLlNUBUm9VdzYHzWEPHd-rogzjqV4jI_GS6evg8rlaHIPVdLEHjiUj2MQuI-Su4n9PFraDYWPCl4lMjflcVE1Bx_iyxA/s1600/starfish.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="500" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdWfEtPTTTxIfcmPXLS4a-rQ3dDI3mReNYt6_pzRpxRppVLGgYTLlNUBUm9VdzYHzWEPHd-rogzjqV4jI_GS6evg8rlaHIPVdLEHjiUj2MQuI-Su4n9PFraDYWPCl4lMjflcVE1Bx_iyxA/s640/starfish.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span><i style="mso-bidi-font-style: normal;">Linckia
laevigata</i> (also known as the Okinawan <a href="https://en.wikipedia.org/wiki/Linckia_laevigata" target="_blank"><span style="color: blue;">blue sea starfish</span></a>) is a bright blue species
of starfish that inhabits the tropical waters of the Indian and Pacific oceans.
It has five cylindrical arms with a bright blue body color and yellow tube feet
(See Image above). The distinctive color comes from a blue pigment called
linckiacyanin as well as some accessory yellow carotenoids. The intense blue coloring
of <i style="mso-bidi-font-style: normal;">L. laevigata</i> likely warns
potential predators of toxicity, although there are no known adverse effects of
the starfish on humans. Interestingly, these animals possess remarkable
regenerative capabilities. For example, the blue seastar can use <a href="https://en.wikipedia.org/wiki/Autotomy" target="_blank"><span style="color: blue;">autotomy</span></a>, or
self-severance of a limb, to escape predation. Moreover, body parts lost to
predators can also be regenerated by the starfish. Due to the aesthetic quality
derived from their brilliant blue color, <i style="mso-bidi-font-style: normal;">L.
laevigata</i> is popular with marine aquarium hobbyists for incorporation in
personal reef aquariums, in spite of requiring slow acclimatization and being
extremely sensitive to changes in temperature, oxygen level and pH.</span></div>
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<span style="font-size: large;"> In light of the regenerative
capacities mentioned above, natural products obtained from <i>L. laevigata</i> were screened in the early 2000s for much sought-after
neuritogenic pharmacological properties. Neuritogenic compounds or neurotrophic
factors, exemplified by <a href="https://en.wikipedia.org/wiki/Nerve_growth_factor" target="_blank"><span style="color: blue;">nerve growth factor</span></a> (NGF), induce neuronal
differentiation, wherein the neurons generate and extend neurites to form a
functional network. For a previously reported example of a neuritogenic
steroid, <a href="https://www.jstage.jst.go.jp/article/antibiotics1968/55/7/55_7_629/_pdf" target="_blank"><span style="color: blue;">see</span></a>. Neuritogenic activity is a vital component in the search for preventative and
therapeutic agents for neurodegenerative diseases such as Alzheimer’s disease.
Linckosides A and B, along with 20 minor congeners, were identified during the
course of the screening campaign. Linckosides share a pentahydroxy-cholestane structural
framework with variable glycosylation patterns. Polyhydroxylated steroid
glycosides are <a href="http://onlinelibrary.wiley.com/doi/10.1002/chem.201301186/abstract" target="_blank"><span style="color: blue;">commonly encountered</span></a> as metabolites in starfishes. However,
across bioactive and naturally occurring steroids, the hydroxylation pattern of
the linckosides is relatively uncommon and hydroxyl groups located at the steroidal
carbogenic position 8 (C8) are particularly rare. Very recently, Biao Yu’s
group at the Shanghai Institute of Organic Chemistry completed the first semisynthetic
preparation of <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b11276?journalCode=jacsat" target="_blank"><span style="color: blue;">linckosides A and B</span></a>. In this post, we will outline their
synthetic approach for oxidative functionalization of the steroid nucleus,
paying particular attention to the strategy for introduction of the C8-hydroxyl
group, an undertaking that is not well-precedented in the synthetic literature.</span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>As depicted above, the partial
synthesis of linckosides A and B begins from the well-known plant-derived
sterol diosgenin, which was converted into the side-chain degradant vespertilin
acetate by a high yielding four-step sequence that was conducted by Yu’s group
on 33-gram scale. The steroidal C7 position was then modified under standard allylic
bromination conditions to provide a functional handle that facilitated eventual
access to the elusive C8 position. In brief, exposure of a C7 <span style="font-family: "symbol";">b-</span>thioarylether intermediate to an
oxaziridine reagent furnished the corresponding sulfoxide as an epimeric
mixture. Subsequent treatment with a mild base at 80 <sup>o</sup>C promoted <i style="mso-bidi-font-style: normal;">cis-</i>elimination of the sulfoxide to
yield a 5,7-diene. The <span style="font-family: "symbol";">D</span><sup>7,8</sup>
unit of unsaturation within the diene system is crucial to the overall strategy
to ultimately hydroxylate the embedded C8 position. However, the more
accessible <span style="font-family: "symbol";">D</span><sup>5,6</sup> olefin was
first selectively epoxidized using methyltrioxorhenium and urea-hydrogen
peroxide and hydrolysis of the resultant oxirane generated the advanced 5<span style="font-family: "symbol";">a</span>,6<span style="font-family: "symbol";">b-</span>diol
intermediate shown above.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The Mukaiyama hydration reaction was
used to install the C8-hydroxyl group onto the steroidal skeleton of the critical
polyhydroxylated <span style="font-family: "symbol";">D</span><sup>7,8</sup> olefin
intermediate. A similarly impressive cobalt-catalyzed Mukaiyama hydration
reaction was previously <a href="http://pubs.acs.org/doi/abs/10.1021/ja202103e" target="_blank"><span style="color: blue;">employed</span></a> by Baran’s group for the stereocontrolled
functionalization of a trisubstituted <span style="font-family: "symbol";">D</span><sup>4,5</sup>
double bond within a complex steroid system (See Scheme above, top panel). The
formamido-diol product thus obtained was then condensed with trimethyl
orthoformate, furnishing a protected intermediate that was suitable for
eventual conversion into the natural product cortistatin A. In the current case
of the linckoside synthetic campaign, Mukaiyama hydration of the aforementioned
key substrate provided the desired C8 <span style="font-family: "symbol";">b-</span>hydroxy
product in a yield that can be considered acceptable in view of the novelty and
exquisite stereoselectivity of the transformation. This critical reaction
likely proceeds through the intermediacy of a cobalt(III)-peroxy intermediate
as the active species, which adds to the least hindered <span style="font-family: "symbol";">p-</span>face of the olefin with Markovnikov selectivity. The reaction
was demonstrated on 330-milligram scale.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Yu’s group appended the final
monosaccharide unit to the western C3-hydroxyl using an <i style="mso-bidi-font-style: normal;">o-</i>alkynylbenzoate building block as the glycosyl donor. This type
of donor, which was developed in Biao Yu’s laboratory, is <a href="http://modernsteroid.blogspot.com/2014/05/chemical-synthesis-of-natural-appetite.html" target="_blank"><span style="color: blue;">activated</span></a> in the
presence of a gold(I) cationic catalyst and, in this example, the 2-deoxy-<span style="font-family: "symbol";">b-</span>glycosidic linkage was constructed with a
high level of stereocontrol, even in the absence of a participatory
C2-neighboring group within the glycosyl donor. A final global deprotection
operation (methanolysis) effectively cleaved the acyl linkages of penultimate synthetic
precursor to yield about 7 milligrams of the neuritogenic natural product
linckoside A, for the first time in a laboratory setting. The chemical
synthesis of linckosides A and B proceeds by a longest linear sequence 32 steps
(44 total) and in 0.5% overall yield. The work is particularly notable as it
provides a good blueprint for oxidative functionalization of the steroid C8
position in the context of a highly complex and biologically relevant synthetic
target molecule. </span><o:p></o:p></div>
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<o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com17tag:blogger.com,1999:blog-7873416017877082260.post-2133986232893180302016-01-02T18:47:00.001-08:002016-01-03T06:10:11.572-08:00Sequestration of Defensive Bufadienolide Steroid Toxins by the Asian Tiger Keelback Snake<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggIhjUHydUMAXqoZeHQQovAzaLH21Ogga0_YxMLW8pg6kk5HkpCysdIJ9yjd8dwHrpSFkThyaetLWnkaV4mu5dw8RnvsSAps4aVvFedAIhViK555BMhmZHIEG6XfTYTrjcvb509L0sGHCG/s1600/Tiger_Keelback.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="426" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggIhjUHydUMAXqoZeHQQovAzaLH21Ogga0_YxMLW8pg6kk5HkpCysdIJ9yjd8dwHrpSFkThyaetLWnkaV4mu5dw8RnvsSAps4aVvFedAIhViK555BMhmZHIEG6XfTYTrjcvb509L0sGHCG/s640/Tiger_Keelback.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The Yamakagashi or Asian Tiger
Keelback Snake (<i style="mso-bidi-font-style: normal;"><a href="http://eol.org/pages/1055425/details" target="_blank"><span style="color: blue;">Rhabdophis tigrinus</span></a></i>,
depicted above) is a venomous Asian snake found in East and Southeast Asia. Its
dorsal color pattern is olive-drab green with black and bright orange crossbars
or spots from the neck down the first third of the body and the average length
of the distinctive snake is about two to three feet. The tiger keelback snake
<a href="https://www.youtube.com/watch?v=7mJOBPgEXv0" target="_blank"><span style="color: blue;">feeds</span></a> mainly on small vertebrates, especially frogs and toads, and possesses unique
defensive glands on the dorsal surface of its neck. These nuchal glands
sequester and contain cardiotonic steroidal toxins known as bufadienolides,
which are also abundant in the skin of toads. This species of snake uses the
steroids primarily as irritants, relying more heavily on the deterrence
provided by these glands. Although venomous, few deaths have been recorded due
to its tendency to display passive anti-predator responses as opposed to
striking.</span></div>
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<span style="font-size: large;"> Researchers Deborah Hutchinson
(Coastal Carolina University), Jerrold Meinwald (Cornell University) and
colleagues have conducted extensive investigations of the chemical composition
of the defensive glands of <i>R. tigrinus</i> (for leading references, see this recent <a href="http://pubs.rsc.org/en/content/articlelanding/2016/np/c5np00108k" target="_blank"><span style="color: blue;">review article</span></a>). A series of fascinating feeding experiments have demonstrated that <a href="https://en.wikipedia.org/wiki/Japanese_common_toad" target="_blank"><span style="color: blue;">Japanese toads</span></a>
(<i>Bufo japonicus</i>) consumed as prey are
the environmental sources of the bufadienolides in the defensive glands of the tiger
keelback snake. Interestingly, snakes that reside on a toad-free Japanese
island (<a href="https://en.wikipedia.org/wiki/Kinkasan" target="_blank"><span style="color: blue;">Kinkasan</span></a>, Miyagi Prefecture) lack these chemicals in their glands, which suggests that the species is unable to biosynthesize the steroidal
toxins. When snakes from Kinkasan were fed toads in the laboratory, they
accumulated bufadienolides in their nuchal glands, indicating that they retain
the ability to sequester defensive compounds from prey. A separate line of
experiments also showed that bufadienolides can be <a href="http://link.springer.com/article/10.1007%2Fs00049-008-0404-5" target="_blank"><span style="color: blue;">provisioned</span></a> to offspring such
that hatchlings are chemically defended prior to their first toad meal. Female <i>R. tigrinus</i> provision bufadienolides to
their offspring in direct proportion to their own level of chemical defense.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDKwSWNuuk0jMaj2zfHQd-qwFasW0WHJg8BwTLZ3IhVATUmV6XNHDbrSF2UE16LKE1Scphw9pjpq2KDJ8aPnM3lUAaKccmRatNlwtjC7shC3khth6B5nVjXtfh2nFCMEZ9whDDikuGwDep/s1600/bufotoxin.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="280" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDKwSWNuuk0jMaj2zfHQd-qwFasW0WHJg8BwTLZ3IhVATUmV6XNHDbrSF2UE16LKE1Scphw9pjpq2KDJ8aPnM3lUAaKccmRatNlwtjC7shC3khth6B5nVjXtfh2nFCMEZ9whDDikuGwDep/s640/bufotoxin.jpg" width="640" /></a></div>
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<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The major bufadienolides that are
accumulated by the tiger keelback snake are derived from <a href="https://en.wikipedia.org/wiki/Bufotoxin" target="_blank"><span style="color: blue;">bufotoxins</span></a> (representative
structures depicted above) that occur in Japanese common (<i style="mso-bidi-font-style: normal;">Bufo</i>) toads. Bufotoxins are variously oxygenated bufadienolides
that bear a suberoylarginine side chain (or similar), appended to the C3 <span style="font-family: Symbol;">b-</span>hydroxyl via an ester linkage. Bufotoxins
themselves have never been found in the snake’s nuchal glands, likely due to
metabolic instability of the ester side chain in conjunction with the fact that
bufotoxins are less toxic than parent bufadienolides such as <a href="http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-13-203" target="_blank"><span style="color: blue;">gamabufotalin</span></a>,
which is the predominant compound accumulated by the snakes. The bufadienolide
steroid toxins sequestered by <i style="mso-bidi-font-style: normal;">R. tigrinus</i><span style="mso-bidi-font-style: normal;">, in general,</span>
are the products of C3 ester hydrolysis (i.e. cleavage of the suberoylarginine
side chain), hydroxylation and/or epimerization.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-71994751888040966592015-12-27T19:21:00.001-08:002015-12-28T03:55:54.560-08:00The Most Concise Enantioselective Approach to Fully Synthetic Steroids Reported To Date<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj037vg76BUWkb4yii9GZZntsReHYA_xYbnbO0quHH5_80x2CIQ5UolG5-GGrbRb11dELntydVoZwfBNp0cviljaigp6hzfFNxrbBWTgvVswb7Lm5wa1EbPwP76Kml4NnCodwJBaGdQrdlR/s1600/deslongchamps.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="556" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj037vg76BUWkb4yii9GZZntsReHYA_xYbnbO0quHH5_80x2CIQ5UolG5-GGrbRb11dELntydVoZwfBNp0cviljaigp6hzfFNxrbBWTgvVswb7Lm5wa1EbPwP76Kml4NnCodwJBaGdQrdlR/s640/deslongchamps.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>This is the 100<sup>th</sup> post at
Modern Steroid Science (begun in late <a href="http://modernsteroid.blogspot.com/2011/12/modern-steroid-science-introduction.html" target="_blank"><span style="color: blue;">2011</span></a>) and, likely, the last of 2015. So it is fitting that we
will provide an overview of one of the most interesting organic synthesis
papers from this year. It is a <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b08528" target="_blank"><span style="color: blue;">report</span></a> from <a href="http://www.umich.edu/~nagornyp/" target="_blank"><span style="color: blue;">Pavel Nagorny’s group</span></a> at the
University of Michigan describing an asymmetric approach to <i style="mso-bidi-font-style: normal;">fully synthetic</i> steroids that proceeds
in just two key steps (4 – 5 total steps, if we account for the preparation of the
building blocks from essentially earth, wind, fire and water). To put this into context, optically
active steroids of a similar level of complexity have been recently prepared in
more like ~20 linear operations. Importantly, the methodology provides access
to unnatural polycyclic molecules that could not be obtained from semisynthetic
derivatization of an abundant sterol and <i style="mso-bidi-font-style: normal;">the
chemistry is practical</i>. No aspect of this expedient, catalytic sequence (to my eye) seems like it
would be limiting with regard to scalability. Indeed, the route has already
been demonstrated on gram-scale by the academic team.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> Back in the 1980s, the laboratory of
Pierre Deslongchamps at the University of Sherbrooke (Quebec) was working on a
rapid approach to fully synthetic steroids. He came up with a <a href="http://www.sciencedirect.com/science/article/pii/S0040403900822571" target="_blank"><span style="color: blue;">one-step synthesis</span></a> starting from a monosubstituted cyclohexenone (eventual A-ring) and
an <span style="font-family: Symbol;">a,b-</span>unsaturated <span style="font-family: Symbol;">b-</span>keto ester (containing the D-ring) that
zips up an androstane system with six contiguous stereogenic centers (see
Scheme above). The chemistry, while highly expedient, has seen limited
practical applications in an industrial or academic setting. A variant of this
technology was used in the first total synthesis of <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.200704959/abstract" target="_blank"><span style="color: blue;">ouabain</span></a>. The anionic
polycyclization of Deslongchamps furnishes racemic products, unless the
starting materials are derived from chiral pool reagents, as was the case for
ouabain. Control over relative stereochemistry at the C/D ring junction positions
(C13/C14) in this complex annulation process is not highly predictable and
seems to involve subtle structural features embedded within the starting
materials. Moreover, the steroidal products thus obtained necessarily bear an ester moiety at the C6 position of the B-ring and a decarboxylation step is
usually required to excise the unneeded functionality. Almost thirty years
later, the anionic polycyclization chemistry first reported by Deslongchamps in
1988 was in need of a bit of a refurbishment.</span></div>
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<o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgk9aSiJHhyphenhyphenH4ogPNuJszCPB8NReeCj21X_STemNWtefjrEJfrZFeONEiyEsxd5SEYxt03bnTFEEau4zulERic-pHX1iiTBdvU2pjwuQSZfyM2AQagyTLZ3C44k7CCpsWif6XIut9PR2Wql/s1600/Nagorny.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgk9aSiJHhyphenhyphenH4ogPNuJszCPB8NReeCj21X_STemNWtefjrEJfrZFeONEiyEsxd5SEYxt03bnTFEEau4zulERic-pHX1iiTBdvU2pjwuQSZfyM2AQagyTLZ3C44k7CCpsWif6XIut9PR2Wql/s640/Nagorny.jpg" width="488" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Nagorny’s two-step steroid synthesis
(shown above) hinges on a challenging asymmetric, diastereoselective Michael
addition between a 2-substituted <span style="font-family: Symbol;">b-</span>ketoester
and a <span style="font-family: Symbol;">b-</span>substituted enone that delivers
a conjugate addition product with vicinal quaternary and tertiary
stereocenters. The reaction employs catalytic levels of inexpensive copper(II)
salts with a noncoordinating counterion in combination with an optically active
bis(4,5-dihydrooxazole) (Box) ligand under solvent-free (neat) conditions. The
substrate scope of the enantioselective Michael addition is outstanding,
generally producing enantiomeric excesses (ee’s) in the low- to
mid-nineties.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Mechanistically, Deslongchamps’
anionic polycyclization protocol first closes the steroid B-ring by a sequential
double-Michael addition. A subsequent intramolecular aldol reaction between the
newly formed cesium enolate and a tethered D-ring cyclopentadione moiety yields
the intact steroid skeleton. Nagorny has cleverly designed his new Michael
addition such that the products obtained from the process competently
participate in a sequenced intramolecular aldol reaction to construct the
B-ring and produce an intermediate that is similar to the penultimate steroid
precursor of Deslongchamps. Nagorny’s approach then benefits from the wealth of
precedent in the steroid literature regarding final C-ring formation via an
additional tandem intramolecular aldol reaction (<a href="http://modernsteroid.blogspot.com/2015/06/a-new-total-synthesis-of-ouabagenin.html" target="_blank"><span style="color: blue;">for example</span></a>), this one between the eventual C8 and
C14 positions. In the event, the double Michael addition developed at the
University of Michigan proceeds with outstanding efficiency and stereocontrol.
Alternate reaction conditions were demonstrated that effectively control the
C/D-ring junction stereocenters, providing divergent, diastereoselective
formation of either a 13<span style="font-family: Symbol;">b-</span> or 13<span style="font-family: Symbol;">a-</span>androstanedione system. The latter annulation product possesses a C5 <span style="font-family: Symbol;">b-</span>oriented hydroxyl
group and the former a <span style="font-family: Symbol;">D</span><sup>5,6</sup>
unit of unsaturation derived from elimination of water. The now readily available structures obtained in this fashion may be suitable for eventual conversion
to bioactive cardenolide or limonoid natural products, classes of steroids that
contain differing configurations of the angular substituent appended to C13.
Notably, the modular process allows for introduction of structural variation at
the C13 position, as well as alteration of the A/D ring size, which could not
be achieved by semisynthetic methods.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>During my initial read of the
Nagorny <i style="mso-bidi-font-style: normal;">JACS</i> <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b08528" target="_blank"><span style="color: blue;">manuscript</span></a>, I was
wondering if the substrate scope that is tolerated by the process would provide access to derivatives that are
functionalized at the C3 position of the steroid A-ring. Nearly all bioactive
sterols and synthetic derivatives thereof possess oxidative functionality at C3.
Indeed, in the course of the first total synthesis of ouabain, Deslongchamps et
al implemented an alkylsilane group appended to the pro-C3 position that required a
late-stage <a href="https://en.wikipedia.org/wiki/Fleming%E2%80%93Tamao_oxidation" target="_blank"><span style="color: blue;">Tamao-Fleming</span></a> oxidation to unmask the latent C3-hydroxyl
functionality. Nagorny provides a clue to the careful reader in this regard by
disclosing the asymmetric Michael example depicted above. Introduction of a
vinyl chloride moiety within the A-ring ketoester building block was shown to
be well-tolerated. The pro-C3 vinyl chloride-containing Michael adduct is obtained in
excellent yield and stereoselectivity, albeit in combination with a simplified <span style="font-family: Symbol;">b-</span>substituted <span style="font-family: Symbol;">a,b-</span>unsaturated
ketone. It will be exciting to see if this highly expedient approach to pharmacologically
privileged steroidal scaffolds will be applied in the coming new year to the
production of architecturally ornate natural products or to new and improved drug
candidates.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com6tag:blogger.com,1999:blog-7873416017877082260.post-82381851754253930062015-12-19T05:54:00.001-08:002015-12-20T12:45:15.185-08:00A High-Throughput Gene Signature Profiling Assay Reveals Withanolides as Lead Compounds for the Chemotherapeutic Treatment of Resistant Prostate Cancer<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjpYq4l76bPxUJy8tHrqg1gjhlcxiNRLby-WZ617sFJ4j9jEQ9C-7Bz76JFd92axYb09YrjXfzLz2DIl289m61xnbgkZwvHYc6OIkKuQN6Sm1iMTDwz6na999Myvf3GsK8E42ta4HHaPfwc/s1600/abiraterone.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="514" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjpYq4l76bPxUJy8tHrqg1gjhlcxiNRLby-WZ617sFJ4j9jEQ9C-7Bz76JFd92axYb09YrjXfzLz2DIl289m61xnbgkZwvHYc6OIkKuQN6Sm1iMTDwz6na999Myvf3GsK8E42ta4HHaPfwc/s640/abiraterone.jpg" width="640" /></a><b><o:p></o:p></b></div>
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<span style="font-size: x-small;"><span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Prostate cancer is a leading killer
of men in North America, second only to heart disease. Proliferation and
metastatic progression of prostate cancer is sensitive to the steroidal hormones
testosterone and dihydrotestosterone, the principal endogenous ligands of the
androgen receptor. For this reason, <a href="https://en.wikipedia.org/wiki/Androgen_deprivation_therapy" target="_blank"><span style="color: blue;">androgen deprivation</span></a> is the standard
first-line therapy used to treat the initial stages of the disease. This therapeutic
regimen involves a reduction of androgen hormones using pharmaceuticals or
surgery in order to prevent prostate cancer cells from growing. In response to
low levels of testosterone, luteinizing hormone-releasing hormone (LHRH) is
produced in the hypothalamus, which activates the synthesis of luteinizing hormone
(LH) by the pituitary gland. LH then travels to the testicles, where it induces the production
of testosterone. LHRH agonists and antagonists both inhibit the formation of LH
in the pituitary gland and thereby lower the amount of testosterone that is made
by the testicles. Reduction of androgens using drug therapy as opposed to surgery
is sometimes referred to as ‘<a href="https://en.wikipedia.org/wiki/Chemical_castration" target="_blank"><span style="color: blue;">chemical castration</span></a>.’</span></span><br />
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<!--StartFragment--><!--EndFragment--><span style="font-size: large;"><span style="font-family: "times" , "times new roman" , serif;"><span style="font-family: "times" , "times new roman" , serif;"><span style="font-family: "cambria";"> </span><span style="font-family: "times" , "times new roman" , serif;">Unfortunately,
the recurrence of androgen-insensitive or</span><span style="font-family: "cambria";"> ‘</span><span style="font-family: "times" , "times new roman" , serif;">castration-resistant prostate cancer
(CRPC)</span><span style="font-family: "cambria";">’ </span><span style="font-family: "times" , "times new roman" , serif;">is often observed in patients. Current treatments</span><span style="font-family: "times" , "times new roman" , serif;"> for CRPC employ radiopharmaceutical, immuno</span></span><span style="font-family: "times" , "times new roman" , serif;">therapeutic and
chemotherapeutic approaches. Among the frontline chemotherapeutic agents for
CRPC is a steroidal antiandrogen marketed under the trade name </span><a href="https://en.wikipedia.org/wiki/Abiraterone_acetate" style="font-family: times, 'times new roman', serif;" target="_blank"><span style="color: blue;">Zytiga</span></a><span style="font-family: "times" , "times new roman" , serif;">. Zytiga
(abiraterone) is an androgen synthesis inhibitor that is used in combination
with another steroid, prednisone. The anticancer drug inhibits cytochrome P450
subtype 17A1</span></span> (<a href="https://en.wikipedia.org/wiki/CYP17A1" target="_blank"><span style="color: blue;">CYP17A1</span></a>), an enzyme with both 17<span style="font-family: "symbol";">a-</span>hydroxylase
and 17,20-lyase activities, which plays a critical role in the steroidogenic
pathway that produces endogenous androgen hormones. Biosynthetically, CYP17A1
catalyzes the C17<span style="font-family: "symbol";">a-</span>hydroxylation of pregnenolone
and progesterone (see Figure above) and also acts upon those hydroxylated metabolites
to excise the side-chain from the steroid nucleus (the lyase activity),
furnishing the intact androgen receptor ligands. Inhibition of CYP17A1 by
Zytiga effectively decreases circulating levels of androgens such as DHEA,
testosterone and dihydrotestosterone. Zytiga also acts as an antagonist of the
androgen receptor and as an inhibitor of the enzyme 3<span style="font-family: "symbol";">b-</span>hydroxysteroid dehydrogenase (3<span style="font-family: "symbol";">b-</span>HSD), further reinforcing its efficacy
as an antiandrogenic treatment for metastatic CRPC. Zytiga therapy generally
prolongs survival by 4.6 months when compared to placebo but durable responses
are not always observed, presumably due to acquired resistance. Therefore, new
therapeutic intervention strategies for resistant PC with an
androgen-depletion-independent phenotype are sought.</span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>A team of natural products
scientists at the University of Arizona and the spin-out company <a href="http://www.nuvogenresearch.com/" target="_blank"><span style="color: blue;">NuvoGen Research</span></a> (Tuscon) has recently developed a unique high-throughput screening
(HTS) approach that utilizes a gene expression profiling methodology. They
refer to the technique as the ‘ArrayPlate’ gene signature assay and it has
enabled the research team to evaluate large libraries of natural product
extracts derived from local Sonoran desert plants to identify chemical agents
that could effectively reverse the androgen receptor (AR) gene signature to its
inactive state. They have utilized the ArrayPlate technology to analyze 18,000
samples and have <a href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00867" target="_blank"><span style="color: blue;">recently disclosed</span></a> the exciting results in the <i style="mso-bidi-font-style: normal;">Journal of Medicinal Chemistry</i>. Of all
the samples tested, the most active was an extract derived from the flowering
plant <i style="mso-bidi-font-style: normal;"><a href="https://en.wikipedia.org/wiki/Physalis_crassifolia" target="_blank"><span style="color: blue;">Physalis crassifolia</span></a></i> (depicted
above). The extract blocked androgen-induced expression of the gene encoding
for prostate-specific antigen (or PSA), as well as others. Bioactivity-guided
fractionation of the <i style="mso-bidi-font-style: normal;">P. crassifolia</i>
extract led to the identification of molecules from a specific subclass of
withanolide-type steroids, the 17<span style="font-family: "symbol";">b-</span>hydroxywithanolides.
These, like the classical <a href="http://modernsteroid.blogspot.com/2011/12/partial-synthesis-of-withanolide-from.html" target="_blank"><span style="color: blue;">withanolides</span></a>, are ergostane-based steroidal lactones.
But unlike the majority of the over 600 natural withanolides characterized to date,
17<span style="font-family: "symbol";">b-</span>hydroxywithanolides possess an <span style="font-family: "symbol";">a-</span>oriented C17 side chain appended to the
steroid D-ring. Additionally, the side chain attachment position (C17) of all
of the active compounds is hydroxylated in the <span style="font-family: "symbol";">b-</span>configuration.
The most active and chemically stable inhibitor of androgen-induced genes was a
semisynthetic 17<span style="font-family: "symbol";">b-</span>hydroxywithanolide derivative
that was later shown to be structurally identical to the natural product
physachenolide C (structure shown above). Physachenolides C and D displayed nanomolar
cytotoxic potency against a panel of human cancer cell lines with a high degree
of selectivity over normal human foreskin fibroblast cells. The molecules were
effective against androgen-sensitive LNCaP cancer cells, as well as the <i style="mso-bidi-font-style: normal;">androgen-insensitive</i> PC-3 cell line.
Given the steroidal nature of the active compounds, it was essential to show
that the cytotoxic biological responses (or lack thereof) were not due to
modulatory androgen receptor activity. It was confirmed that physachenolide D
had no effect on androgen binding to the AR, while dihydrotestosterone
inhibited binding with an IC<sub>50</sub> of 13 nM.</span><o:p></o:p></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgq8eFHke5WLONdD8vIPBL_iBo_Tbjn-gZMerSkR85BpkvqBLWVTCI_zI8HtCzEhauxbiNkyMXgBcv0KfMYRlHHYVnbNMVabGJ8iUTFHVAGv6wq8yvId8bbzX4U5-bayTiwQB-vNin6Uxim/s1600/data.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgq8eFHke5WLONdD8vIPBL_iBo_Tbjn-gZMerSkR85BpkvqBLWVTCI_zI8HtCzEhauxbiNkyMXgBcv0KfMYRlHHYVnbNMVabGJ8iUTFHVAGv6wq8yvId8bbzX4U5-bayTiwQB-vNin6Uxim/s640/data.jpg" width="536" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Adapted from: R. M. Kris, A. A. L. Gunatilaka and co-workers. <i>J. Med. Chem. </i><b>2015</b>, <i>58</i>, 6984.</span></td></tr>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Prior to in vivo efficacy evaluation
of physachenolide C, the maximum tolerated dose (MTD) was determined and then pharmacokinetic
studies were conducted using variously formulated drug substance dosed via
intraperitoneal (IP), gastric gavage (GG) and subcutaneous (SC) routes of
administration. Ultimately, it was determined that efficacy studies could be
conducted optimally using the SC route with ‘Trappsol,’ a formulation excipient
recommended for administering hydrophobic compounds and approved by the FDA for
injection into humans, as the vehicle. Two human PC murine xenograft models
were conducted: the first mimicked an androgen-dependent disease using mouse inoculation
with cancerous LNCaP cells and the second was an androgen-independent model
using PC-3 cells. The results from the LNCaP xenograft experiment (reproduced
above from <i style="mso-bidi-font-style: normal;">J. Med. Chem.</i> <b style="mso-bidi-font-weight: normal;">2015</b>, <i style="mso-bidi-font-style: normal;">58</i>, 6984.) showed that physachenolide C was able to reduce tumor
growth in a dose-dependent manner but did not invoke a synergistic effect when
applied in combination with <a href="https://en.wikipedia.org/wiki/Docetaxel" target="_blank"><span style="color: blue;">Taxotere®</span></a>, which is the current standard of care
for CRPC. A similar level of efficacy was observed in the androgen-independent PC-3
xenograft model. As is often the case with cytotoxic agents, the therapeutic safety
window is a key parameter. As the authors put it: “<i>…[compound] <b style="mso-bidi-font-weight: normal;">6</b> was able to reduce tumor growth…in
the mice that did not die from the toxicity.</i>” Indeed, at a dose of 25 mg/kg physachenolide
C, three of the eight mice died due to drug toxicity (Figure above, lower panel). At 25 mg/kg
physachenolide C, dosed in combination with Taxotere®, all eight of the mice
succumbed. All other deaths observed in the course of the study were due to
euthanization because of tumor size. The authors speculate on a potential
mechanism of action for the observed potent and selective anti-PC activity
involving <a href="https://en.wikipedia.org/wiki/TRAIL" target="_blank"><span style="color: blue;">TRAIL</span></a>-induced apoptosis of carcinoma cells.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-91827112267295265602015-12-15T14:07:00.000-08:002015-12-16T07:27:18.112-08:00The First Chemical Synthesis of Limonin: Supply Chain Implications for Future Clinical and Toxicological Testing of Limonin Glucoside<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJrtu3Uk6eYY5vkpo9r9pAPJYPKV_lWLrqmAetMEaTMZvXvMZMNFWpvuYj1prDxNuugCzH2J9N5kqeDsReIN0VGeIEkjykTwmoVAOzFSk4JlUcO_GHsvslKEGZcJn0dXUc_7h9m7DYKLtg/s1600/structures.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="582" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJrtu3Uk6eYY5vkpo9r9pAPJYPKV_lWLrqmAetMEaTMZvXvMZMNFWpvuYj1prDxNuugCzH2J9N5kqeDsReIN0VGeIEkjykTwmoVAOzFSk4JlUcO_GHsvslKEGZcJn0dXUc_7h9m7DYKLtg/s640/structures.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In a previous series of posts at
this site, we <a href="http://modernsteroid.blogspot.com/2015/11/citrus-limonin-glucoside.html" target="_blank"><span style="color: blue;">highlighted</span></a> a placebo-controlled human study with purified
limonin glucoside (LG) in which significant health benefits were observed. The
disclosure of these exciting results by the U.S. Department of Agriculture (USDA) provoked a thought exercise
concerning the downstream supply chain issues that this development program
will likely face. The USDA team led by Darshan Kelley was able to obtain about
100 grams of high-purity LG through development and execution of an optimized
<a href="http://modernsteroid.blogspot.com/2015/12/isolation-of-high-purity-limonin.html" target="_blank"><span style="color: blue;">extraction process</span></a> starting from molasses, a by-product obtained from citrus
processing waste streams. However, in order to conduct additional clinical and
toxicological testing of this unique limonoid natural product, multiple
hundreds of grams (and likely kilograms) of API will be required at various stages. Given the
architectural complexity of limonin and related substances derived thereof,
does partial or total chemical synthesis provide a viable sourcing alternative?
In this post, we will examine the recently disclosed <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201503794/abstract" target="_blank"><span style="color: blue;">first total synthesis</span></a> of
racemic limonin and compare the productivity of this process with that of the
optimized isolation from citrus molasses that was previously developed by the
USDA.</span></div>
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<span style="font-size: large;"> We should begin by noting that the
completion of the first total synthesis of limonin is an exceptional
accomplishment, given that this limonoid has been known as the bitter principle
derived from citrus for over 150 years. Limonin, an oxidatively fragmented
17-furylandrostane, is a highly complex small molecule, on par with other
notable limonoid family members including <a href="http://modernsteroid.blogspot.com/2015/09/recent-synthetic-work-on-triterpenoid.html" target="_blank"><span style="color: blue;">azadirachtin</span></a> and <a href="http://modernsteroid.blogspot.com/2014/10/libiguin-a-novel-phragmalin-limonoid.html" target="_blank"><span style="color: blue;">libiguin A</span></a>. The
detailed molecular structure of limonin remained unknown until 1960, when a
determination was finally <a href="http://link.springer.com/article/10.1007%2FBF02170251" target="_blank"><span style="color: blue;">made</span></a> using chemical derivatization and X-ray
diffraction methods. More than fifty years later, in 2015, we now can begin to
discuss the state-of-the-art laboratory methods that enabled the first and only
chemical synthesis of limonin. The total synthesis of limonin, reported by the
Japanese team led by Shuji Yamashita and Masahiro Hirama, can roughly be broken
down into two synthetic “phases,” as outlined in the Figure above. In phase 1,
the 4,4,8-trimethylandrostane steroidal framework is constructed from readily
available geraniol. The critical synthetic operations that led to the
successful execution of phase 1 include a tandem radical polycyclization using Barry
Snider’s manganese(III)-mediated <a href="http://pubs.acs.org/doi/abs/10.1021/cr950026m?journalCode=chreay" target="_blank"><span style="color: blue;">chemistry</span></a>, followed by a standard Robinson
annulation to forge the steroid A-ring. This portion of the route provides
access to the requisite androstane system containing the appropriate
methylation and oxidation patterns for the completion of the target structure.
However, 17 synthetic steps are required to produce the desired intermediate
for initiation of phase 2 of the route, oxidative fragmentation and elaboration
of the eastern D-ring and western A-ring. The identification of an abundant,
plant-derived sterol that contains oxygenated functionality at carbon positions
3, 7 and 19, to be used as a starting material for a semisynthetic process, would
significantly improve the practicality of the overall approach by reducing the step
count. Phase 2 of the Tohoku University process is truly innovative and
provides a pioneering blueprint for late-stage synthetic manipulations
involving complex limonoid systems.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0hkp6s57Kv1jsmkhptjLUtIemMWHaNTDnvkM2m2ed_YLZWR2t_bdarxa8cbnvmu-_uNx_wYygwuV8Y6LD1tgrmiVxRTjVVWm2li4pIIwt3qHc6dPr7N8k_pFUSPcdwTRt5LRgO7IM97Jp/s1600/precedent_rev.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="622" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0hkp6s57Kv1jsmkhptjLUtIemMWHaNTDnvkM2m2ed_YLZWR2t_bdarxa8cbnvmu-_uNx_wYygwuV8Y6LD1tgrmiVxRTjVVWm2li4pIIwt3qHc6dPr7N8k_pFUSPcdwTRt5LRgO7IM97Jp/s640/precedent_rev.jpg" width="640" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The overwhelming lack of synthetic
progress reported towards the limonin system prior to Yamashita and co-workers’
2015 disclosure is striking. In the mid-1970s and early 1980s, a German group
at ETH Zürich led by Walter Graf published the synthesis of a model compound (shown
above) incorporating the eastern substructure of limonin, albeit lacking the
14,15-epoxy functionality. Almost two decades later, in the late 1990s, the
research group of Ernesto Suárez (Spain) <a href="http://pubs.acs.org/doi/abs/10.1021/jo962252h" target="_blank"><span style="color: blue;">reported</span></a> the synthesis of a similar
model system bearing the western limonin system. The photochemical reaction that
was developed by Suárez is a fragmentation process wherein irradiation of a
hemiketal hydroxyl with visible light in the presence of oxidants promotes
peroxidation of an initially formed carbon-centered radical to furnish a peroxy
radical. The peroxy radical reacts further with iodine to give an alkoxy
radical and iodoxyl radical. The alkoxy radical finally engages a proximally
situated, unactivated C-H position in intramolecular functionalization through
the intermediacy of a six-membered cyclic transition state to produce the desired
limonin tetrahydrofuran. To the best of my knowledge, these are the only
published protocols for limonin synthesis that were available to the Tohoku
University team at the outset of their studies. The group did indeed make use
of the Suárez precedent (see below), providing a fascinating late-stage example
of the tandem fragmentation/C-H functionalization process on, without question,
the most complex substate reported to date.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The portion of the inaugural limonin
synthesis that is truly worthy of highlighting is the ‘phase 2’ oxidative
fragmentation and elaboration of the androstane D-ring, a 13<span style="font-family: "symbol";">a-</span>cyclopentenone, into the intact eastern
limonin substructure. The synthetic technology depicted in the Scheme above
will undoubtedly guide and enable future synthetic studies targeting limonoid
systems that were previously considered synthetically inaccessible due to
excessive chemical complexity. The overall conversion is initiated by
installation of a butenolide system via a Stille coupling protocol that has
been <a href="http://modernsteroid.blogspot.com/2015/06/a-new-total-synthesis-of-ouabagenin.html" target="_blank"><span style="color: blue;">used previously</span></a> to synthesize cardenolide natural products. Singlet oxygen
[4+2] cycloaddition then simultaneously functionalizes the steroidal C13 and
C17 positions in a single operation. As originally reported by <a href="http://pac.iupac.org/publications/pac/pdf/1986/pdf/5805x0799.pdf" target="_blank"><span style="color: blue;">Karel Wiesner</span></a> in
the 1980s, the butenolide is a latent synthetic form of a furan ring system and,
notably, this reductive conversion could be accomplished without harming the
sensitive endoperoxide. Fortunately, upon exposure to a ruthenium(II) catalyst
as described by the Nobel laureate <span style="color: blue;"><a href="http://pubs.acs.org/doi/abs/10.1021/jo00283a023" target="_blank"><span style="color: blue;">Noyori</span></a> </span>in the late 1980s, the endoperoxide functionality
was successfully fragmented to an oxy radical intermediate that underwent
further conversion to a bis-epoxide. Then, upon exposure of the intermediary
bis-epoxide to mildly acidic silica gel, a suprafacial 1,2-hydride shift
ensued, giving rise to an epoxy ketone albeit with the undesired stereochemical
configuration at C17. Base-mediated epimerization of the C17 position followed
by a Baeyer-Villiger ring-expansion of the five-membered D-ring finally
completed the stereocontrolled construction of a fully elaborated limonin
eastern substructure, suitably functionalized for late-stage oxidative manipulation
of the A-ring.</span><o:p></o:p></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhuhBaCEi4Dxvt_5R7TTTwDXnNxX6eFBqm3XKLvgXgSrnTm2CbYbJNyXd95DAZECPhagrqQFIUnLfChBZoL0PJkJCF3Wk9rvy2F2MirUPgXUY0ZuHO18XMkVQKk5p36AOS3q64wJComUp-C/s1600/west+side_rev.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="508" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhuhBaCEi4Dxvt_5R7TTTwDXnNxX6eFBqm3XKLvgXgSrnTm2CbYbJNyXd95DAZECPhagrqQFIUnLfChBZoL0PJkJCF3Wk9rvy2F2MirUPgXUY0ZuHO18XMkVQKk5p36AOS3q64wJComUp-C/s640/west+side_rev.jpg" width="640" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>As noted above, in the course of
their synthetic endgame, Yamashita and Hirama et al directly applied the Suárez
protocol, as reported in the 1989 <i style="mso-bidi-font-style: normal;">J. Org.
Chem.</i> manuscript, without noticeable modification. This remarkably complex
example of the Suárez reaction, demonstrated on 4.4-milligram scale, behaved
‘as advertised,’ and the desired oxidative fragmentation product was obtained
and processed further in crude form. The final two synthetic operations,
involving deprotection and redox manipulation of C7, ultimately furnished 600
micrograms of purified limonin that was identical in all respects to material
derived from natural sources. The first total synthesis of <span style="font-family: "symbol";">(+/-)</span>-limonin proceeded in 35 total steps
starting from geraniol. Nearly half of those synthetic operations were required
for total synthesis of the steroid framework (i.e. ‘Phase 1’). The oxidative rearrangement
of the steroid A- and D-rings, which I have referred to here as ‘Phase 2,’ is indeed
groundbreaking and will likely facilitate the synthesis other similarly
complex, bioactive limonoid architectures. <o:p></o:p></span></div>
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<span style="font-size: large;"> So how does this work impact the
supply chain question that was advanced at the top of this post? As I have
stated <a href="http://modernsteroid.blogspot.com/2015/11/a-formal-synthesis-of-neem-limonoid.html" target="_blank"><span style="color: blue;">elsewhere</span></a>, the metric for the degree of success of a synthetic project
can be quantified by answering the question: ‘<span style="color: #1a1a1a;">How does this
technology compare with extraction from natural sources or microbial production
by an optimized fermentation process?’ Academic synthetic work can be both
virtuosic in its educational value for students, and, at the same time,
completely impractical as judged by industrial standards. The best synthetic
work is academically and aesthetically satisfying, but also useful in the lab
on a meaningful scale. In the case of limonin, similar to the infamous example provided
by azadirachtin, the state-of-the-art in synthetic chemical methodology falls
short when compared with isolation of drug substance from natural sources. As
noted previously, using the optimized </span><a href="http://modernsteroid.blogspot.com/2015/12/isolation-of-high-purity-limonin.html" target="_blank"><span style="color: blue;">USDA extraction process</span></a><span style="color: #1a1a1a;"> and estimating
conservatively, approximately two liters of citrus molasses can be processed in
four to six weeks to produce about 18 grams of high-purity limonin glucoside,
suitable for human studies. Moreover, the molasses feedstock is a worthless
by-product of citrus processing that juice producers are happy to dispose of.
On the other hand, the chemical synthesis of limonin in racemic form, in all likelihood,
required several man-years of effort in order to produce less than one
milligram. This comparison is, admittedly, harsh and perhaps unfair, given that
the two research groups involved in the work obviously had entirely different research
goals. However, the comparison is nonetheless instructive and should be taken
into consideration before it is </span><a href="http://blogs.sciencemag.org/pipeline/archives/2010/08/06/organic_chemistry_a_lack_of_challenges" target="_blank"><span style="color: blue;">asserted</span></a><span style="color: #1a1a1a;"> that organic chemistry has ‘</span><a href="https://www.chem.tamu.edu/rgroup/romo/images/romo_new_voices_chemistry.pdf" target="_blank"><span style="color: blue;">matured</span></a><span style="color: #1a1a1a;">,’
and that any molecule can be synthesized, given the appropriate time and resources.
The challenge presented by a chemical synthesis of limonin disputes that fundamentally flawed notion.</span></span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-52925165138020874682015-12-06T07:12:00.000-08:002015-12-06T16:47:53.559-08:00Isolation of High-Purity Limonin Glucoside from Molasses, a By-Product Obtained from Citrus Processing Waste Streams<div class="separator" style="clear: both; text-align: center;">
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDtwlh3udv8yclcimMnvtyMrm4tH62btpm_po-zYYY241s7AIruq-9NxZ2-jzpBDMwKFiYGIW9kKhwO1qUnH68PwyrwaMq6sYJUR6-lM6m2RPYadv_uM8Adr10ZcWQAozB8O0SqlLFzpct/s1600/HPLC.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="546" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDtwlh3udv8yclcimMnvtyMrm4tH62btpm_po-zYYY241s7AIruq-9NxZ2-jzpBDMwKFiYGIW9kKhwO1qUnH68PwyrwaMq6sYJUR6-lM6m2RPYadv_uM8Adr10ZcWQAozB8O0SqlLFzpct/s640/HPLC.jpg" width="640" /></a></div>
<span style="font-size: large;"> In the previous <a href="http://modernsteroid.blogspot.com/2015/11/citrus-limonin-glucoside.html" target="_blank"><span style="color: blue;">post</span></a>, we highlighted
a study from the USDA that examined the health benefits of limonin glucoside
(LG) supplementation, as indicated by circulating levels of blood lipids,
glucose and biomarkers of chronic inflammatory diseases, in human subjects. As
can be seen from the complicated HPLC trace shown above, recovery of pure
limonoid glucosides from natural sources in order to fund these types of human
studies is not a trivial undertaking. Moreover, given the molecular complexity
of most limonoids, chemical synthesis may not necessarily provide a viable supply
chain alternative. In my rough estimation, the USDA study required the sourcing
of about one hundred grams of limonin glucoside containing very low levels of its
corresponding aglycone, <a href="https://en.wikipedia.org/wiki/Limonin" target="_blank"><span style="color: blue;">limonin</span></a>. While limonin glucoside is tasteless, limonin
tastes extremely bitter and beverage concentrations of >6 mg/liter render
citrus juice unacceptable to consumers. In fact, the <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2621.2002.tb08876.x/abstract" target="_blank"><span style="color: blue;">original isolation of LG</span></a> by
the USDA produced material that was insufficiently pure. Taste tests of the
resulting formulated beverages indicated that they were too bitter for human consumption
due to limonin aglycone contamination. In this post, we will outline and
discuss the optimized citrus extraction process that was eventually developed in
order to support the human LG supplementation study.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXZY8RZKc3OgqXeli4hFq7NvT5b84FbgNxlQDyIqxMSGinaIiH5ScmV7HTxl0-h1CEe3OxCldT1uE1ZeaodfszZvP9-l7L7JTBAwAiYhiUWwk7bHqhEsV02U1vThRKdHchXOpryulyGUkE/s1600/extraction.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="390" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXZY8RZKc3OgqXeli4hFq7NvT5b84FbgNxlQDyIqxMSGinaIiH5ScmV7HTxl0-h1CEe3OxCldT1uE1ZeaodfszZvP9-l7L7JTBAwAiYhiUWwk7bHqhEsV02U1vThRKdHchXOpryulyGUkE/s640/extraction.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Citrus <a href="https://en.wikipedia.org/wiki/Molasses" target="_blank"><span style="color: blue;">molasses</span></a>, a thick, viscous
liquid that is dark brown to almost black in color, is a major by-product of
citrus processing. The fresh pulp obtained after pressing the fruit is mixed
with lime (calcium oxide) and pressed to remove moisture. The resulting liquid
is then filtered to remove the larger particles, sterilized by heating and
concentrated to produce molasses. Citrus molasses is often fed to animals or
fermented to produce ethanol, yielding meager profit margins for juice
producers. Interestingly, <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2621.1995.tb05634.x/abstract" target="_blank"><span style="color: blue;">HPLC and LC/MS analyses</span></a> (see Figure above, left-hand
panel) have shown that limonoid glucosides are present in significant amounts
in molasses. A preparative scale method for recovery of LGs from citrus
molasses was <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2621.2002.tb08876.x/abstract" target="_blank"><span style="color: blue;">disclosed</span></a> in 2002 by Thomas Schoch, Gary Manners and Shin Hasegawa
at the USDA. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>A schematic flow diagram of the USDA process is reproduced in the Figure above. To begin, one to two liters of crude
molasses is diluted with distilled water and the resulting solution is
centrifuged. The supernantant thus obtained is then loaded onto a column
containing Dowex 50WX4-100 resin and the outflow of the column is directly
connected to a second column containing SP70 Sepabeads. Ethanol is used to
elute the partially purified mixture from the second column. The Dowex column,
a sulfonic acid cation-exchange resin, is intended to remove colored compounds
present in molasses. The Sepabeads, which are a divinylbenzene copolymer
(basically polystyrene), subsequently absorb and remove hydrophobic components.
The eluent solution from the SP70 column is then adjusted to pH 6.5 with dilute
aqueous sodium hydroxide in order to maintain consistent chemical reactivity
and chromatographic behavior within the partially purified LG mixture.<o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The LG solution is then loaded onto
a Q-Sepharose column and the column is eluted with an aqueous sodium chloride
gradient. The Q-Sepharose stationary phase is a quaternary ammonium resin,
designed to bind negatively charged compounds. Limonin glucosides are
relatively acidic (pK<sub>a</sub>~2.8) and are therefore anionic at pH 6.5.
The salt gradient elutes the negatively charged limonoids in order of
decreasing pK<sub>a</sub>, enabling separation of the LGs from things like
flavonoids, which are phenolic and less acidic. The resulting LG-containing
fractions are then subjected to a second Dowex/SP70 treatment and the solvent is
finally removed by iterative co-evaporation with ethanol to furnish a
golden-brown limonoid powder. The method outlined above can produce about ten
grams of >60% pure limonoid glucoside feedstock per week. Further
re-purification of the powder by recrystallization from warm water yields
semi-pure limonin glucoside, contaminated predominantly with unacceptably high
levels of the corresponding aglycone, limonin. In order to remove the bitter
limonin impurity, an HPLC ‘polishing’ method utilizing food grade solvents
(aqueous ethanol) was <a href="http://naldc.nal.usda.gov/catalog/23189" target="_blank"><span style="color: blue;">developed</span></a>. Using a 75 x 300 mm C18 column, the method is
capable of processing 20 grams of material per run in less than three hours.
Recovery of the purified limonin glucoside following evaporation of solvent is
nearly perfect (~94%) and the limonin content is consistently reduced to
<0.10% by weight. Estimating conservatively, it looks like about two liters
of molasses could be processed in four to six weeks to produce around 18 grams
of high-purity limonin glucoside, suitable for human studies. By industrial
standards, this type of productivity would be considered relatively
low-throughput, given that a dose of 500 mg/day/patient is required for
beverage supplementation studies. But, in the case of limonin or a related API
of similar molecular complexity, does partial or total chemical synthesis
offer a more scalable alternate supply chain approach to support downstream
clinical programs? In a forthcoming post, we will examine the first and only
reported <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201503794/abstract" target="_blank"><span style="color: blue;">chemical synthesis of limonin</span></a>, disclosed in the summer of 2015 by
researchers at Tohoku University in Japan. We will then directly compare the
synthetic efficiency achieved by the world’s best organic chemists, using
state-of-the-art methods, with that of recovery from citrus processing waste
streams, in terms of practicality, cost and overall effort.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-91478311922844678022015-12-03T17:12:00.002-08:002015-12-04T03:52:52.855-08:00On Selective Functionalization of Polyhydroxylated Terpenoids: The First Chemical Synthesis of the Natural Insecticide, Ryanodine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2dytxxhy8auc0JjuD4sTdPnoBUlXBAoxxm-uhogeeh92JKfSO4Ac1a3XOnt5DNnTIImtLk7l5TgINPlS4JVpuyHVmeRkdxPd7J3h-UZZfnnFBtzaS07_JegBrUHlz2D0YLjn1AkluI7hk/s1600/ryanodine.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="568" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2dytxxhy8auc0JjuD4sTdPnoBUlXBAoxxm-uhogeeh92JKfSO4Ac1a3XOnt5DNnTIImtLk7l5TgINPlS4JVpuyHVmeRkdxPd7J3h-UZZfnnFBtzaS07_JegBrUHlz2D0YLjn1AkluI7hk/s640/ryanodine.jpg" width="640" /></a></div>
<div style="text-align: justify;">
<span style="font-size: large;"><span style="font-family: "times";"> As I was working to wrap my head around the recent <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201503794/abstract" target="_blank"><span style="color: blue;">total synthesis</span></a> of <a href="https://en.wikipedia.org/wiki/Limonin" target="_blank"><span style="color: blue; text-decoration: none; text-underline: none;">limonin</span></a> in preparation for a forthcoming post, I was surprised to see that the <a href="http://onlinelibrary.wiley.com/doi/10.1002/chem.201503641/abstract" target="_blank"><span style="color: blue; text-decoration: none; text-underline: none;">first total synthesis</span></a> of the naturally occurring insecticide <a href="https://en.wikipedia.org/wiki/Ryanodine" target="_blank"><span style="color: blue; text-decoration: none; text-underline: none;">ryanodine</span></a> was published by Masayuki Inoue’s group at the University of Tokyo. One of the impressive aspects of this work is that it is an asymmetric chemical synthesis of </span><span style="font-family: "symbol";">(+)-</span><span style="font-family: "times";">ryanodine and not the related polyol, <i>ryanodol</i>. Ryanodine is the ester product derived from regioselective esterification of ryanodol with 1<i>H-</i>pyrrole-2-carboxylic acid. Importantly, ryanodine binds to the ryanodine receptor, an intracellular <a href="https://en.wikipedia.org/wiki/Ryanodine_receptor" target="_blank"><span style="color: blue; text-decoration: none; text-underline: none;">calcium channel</span></a>, with high potency whereas ryanodol does not. Ryanodol was synthesized in racemic form by Pierre Deslongchamps’ group in the late 1970s (<a href="http://www.scripps.edu/baran/images/grpmtgpdf/Shenvi_Apr_04.pdf" target="_blank"><span style="color: blue; text-decoration: none; text-underline: none;">43 steps from carvone</span></a>), but the group was not able to reach ryanodine because esterification of ryanodol occurs at an undesired position. Inoue’s synthetic strategy allows selective ‘blocking’ of the hemiketal -OH group along with 5 of the 6 hydroxyls of the ‘ryanoid’ polyol, such that the hindered C3-hydroxyl can be selectively functionalized en route to the target structure. Similar protecting group strategies were required in order to synthesize certain complex polyhydroxylated steroids including <a href="http://modernsteroid.blogspot.com/2015/06/a-new-total-synthesis-of-ouabagenin.html" target="_blank"><span style="color: blue;">ouabain</span></a>, <span style="color: blue;"><a href="https://en.wikipedia.org/wiki/Ecdysone" target="_blank"><span style="color: blue;">ecdysone</span></a> </span>and, more recently, <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b11276" target="_blank"><span style="color: blue;">linckoside A</span></a>. At any rate, the inaugural total synthesis of a natural product in 2015 that has been known since 1948, and which possesses important pharmacological activity, is indeed a great achievement. Ryanodine is clearly not a steroid so I won’t discuss its synthesis in any degree of detail here, but an overview of the successful protecting group strategy and endgame protocol is diagrammed above.</span></span></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-27668640897900841812015-11-27T06:32:00.001-08:002015-11-27T12:41:05.706-08:00Citrus Limonin Glucoside Supplementation Decreases Biomarkers of Disease and Inflammation in Humans<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiA1YWe6X3oa8-l0GRK3vs5hovfOUY9QKfvaj41fWp8hr_atV5Gm_39aT8SMwVrtKO_N65Wp-iX87GXY0p2E_xV7Z_qmlXEdnwn-QnQL2lBliPPcqXrwLh-3kSKwj6-XmLloyQ06RfoFiS4/s1600/limonin.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="582" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiA1YWe6X3oa8-l0GRK3vs5hovfOUY9QKfvaj41fWp8hr_atV5Gm_39aT8SMwVrtKO_N65Wp-iX87GXY0p2E_xV7Z_qmlXEdnwn-QnQL2lBliPPcqXrwLh-3kSKwj6-XmLloyQ06RfoFiS4/s640/limonin.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>It is commonly known that fresh
fruits should be part of a healthy, balanced diet. Epidemiological studies reinforce
this notion, revealing that increased consumption of fresh fruits is associated
with reduced risk of diabetes, cardiovascular disease and cancer. Are there
specific phytochemicals and biomolecules present in fruits, aside from
well-known and well-studied flavonoids and <a href="https://en.wikipedia.org/wiki/Vitamin_C" target="_blank"><span style="color: blue;">vitamin C</span></a>, that elicit these
demonstrated health benefits in humans? Identification of fruit-derived
nutraceutical components could provide access to new dietary supplements for
prevention and/or treatment of various chronic diseases.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span><a href="http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201001218/abstract" target="_blank"><span style="color: blue;">Citrus limonoids</span></a> are highly
oxygenated triterpenoids that occur in a variety of citrus tissues in
significant quantities (<i style="mso-bidi-font-style: normal;">up to 900 ppm in
orange juice</i>). Limonoids exist in citrus juice and tissues as water-soluble
glucosides. Citrus seeds and peel extract contain water-insoluble limonoid
aglycones. Certain limonoid aglycones such as the flagship member of the
limonoid natural product family, <a href="https://en.wikipedia.org/wiki/Limonin" target="_blank"><span style="color: blue;">limonin</span></a>, are responsible for the development
of delayed bitterness in citrus. Limonin was isolated in the 1840’s but its
precise chemical structure was not elucidated until 1960, when a collaborative
team that included Derek Barton and E. J. Corey <a href="http://link.springer.com/article/10.1007%2FBF02170251" target="_blank"><span style="color: blue;">solved</span></a> the structure using
chemical derivatization and X-ray diffraction methods. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>A recent <a href="http://www.sciencedirect.com/science/article/pii/S1756464614003764" target="_blank"><span style="color: blue;">report</span></a> from Darshan Kelley and co-workers at the USDA has
demonstrated that consumption of a specific limonoid natural product, limonin
glucoside (structure shown above), effectively reduces plasma concentrations of markers for chronic
inflammatory diseases in human subjects. The authors examined the effects of
limonin glucoside consumption on blood lipids, lipoproteins and liver enzymes.
In this study, twelve-ounce drinks containing 250 milligrams of limonin
glucoside dissolved in aqueous citrate buffer solution were consumed twice per
day by subjects. The drinks were orange-flavored and contained some vitamin C
and zero calories. The double blind study was also placebo controlled. Notably,
at a dose of 500 mg/day, limonin glucoside had no specific adverse effects and
the drinks were well-tolerated. Moreover, the drinks effectively reduced serum
concentrations of several hepatic markers that are recognized to be associated
with obesity and inflammation. The reduction in markers included gamma-glutamyl
transferase (<a href="https://en.wikipedia.org/wiki/Gamma-glutamyl_transpeptidase" target="_blank"><span style="color: blue;">GGT</span></a>, 34%), alanine aminotransferase (<a href="https://en.wikipedia.org/wiki/Alanine_transaminase" target="_blank"><span style="color: blue;">ALT</span></a>, 13%) and alkaline
phosphatase (<a href="https://en.wikipedia.org/wiki/Alkaline_phosphatase" target="_blank"><span style="color: blue;">ALP</span></a>, 10%). Circulating concentrations of GGT, ALT and ALP are
elevated in several human diseases including alcoholic and nonalcoholic fatty
liver disease and metabolic syndrome. The authors note that one etiological
link among these conditions is increased oxidative stress and inflammation and
that future studies are warranted to examine the potential of limonoids to
prevent or reverse these diseases.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> In forthcoming posts, we will
examine the manner in which the authors of the study executed the deceptively challenging
task of sourcing hundreds of grams of a highly complex natural product with
purity in excess of 99.93%. We will also compare the USDA’s isolation method (extraction
from citrus molasses) with the state-of-the-art in total chemical synthesis.
The first <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201503794/abstract" target="_blank"><span style="color: blue;">total synthesis</span></a> of racemic limonin was very recently disclosed by
Shuji Yamashita’s and Masahiro Hirama’s research groups at Tohoku University
(Japan). Limonin provides an outstanding case study by which to compare divergent
supply chain approaches to sourcing structurally complex API’s.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com4tag:blogger.com,1999:blog-7873416017877082260.post-20864925374844477342015-11-22T15:49:00.000-08:002015-11-22T17:25:20.174-08:00A Bioprecursor Prodrug Approach to Neuroselective Delivery of Estradiol to the Brain<!--[if gte mso 9]><xml>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Estrogen deficiency in the human
brain is observed as a rather serious side effect of preventative <a href="https://en.wikipedia.org/wiki/Oophorectomy" target="_blank"><span style="color: blue;">oophorectomy</span></a>,
the surgical removal of ovaries, which is increasingly performed today in
gynecological oncology. The deficiency arises because women who have had
bilateral oophorectomy surgeries lose most of their ability to produce the
hormones estrogen and progesterone. The sudden inability to produce estrogen
initiates what is referred to as ‘<a href="https://en.wikipedia.org/wiki/Menopause#Surgical_menopause" target="_blank"><span style="color: blue;">surgical menopause</span></a>,’ which is generally
accompanied by an abrupt onset of neurological and psychiatric maladies
triggered by the hormonal deficiencies. Those menopausal indications are
commonly addressed through equine estrogen-based hormone replacement therapy. Unfortunately,
hormone replacement therapy is not desirable for all symptomatic women due to
the peripheral side effects and tumor-promoting properties of estrogen.
Therefore, the invention and commercialization of a safe and effective
treatment of the adverse consequences of estrogen deficiency in the brain, which
include depression and impaired sexuality, is a major unmet medical need.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgWLIfweX3-EIBRdUSSON5YebyXq6k01LsfZ96Ub2cW5BS83PHl10S_1tbIPxxBwCVkbmJiPMNPkrt2hkliJe9ROPkYPLIuOUr_cFJ3EI8KtjFE3oxn-N12Xk1lDG5cYbtdaJNKi8W1PZ84/s1600/DHED.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="576" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgWLIfweX3-EIBRdUSSON5YebyXq6k01LsfZ96Ub2cW5BS83PHl10S_1tbIPxxBwCVkbmJiPMNPkrt2hkliJe9ROPkYPLIuOUr_cFJ3EI8KtjFE3oxn-N12Xk1lDG5cYbtdaJNKi8W1PZ84/s640/DHED.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The development of brain-selective
estrogen therapies has been a formidable medical challenge. Recent efforts to generate
neuroselective estrogen receptor modulators have been achieved through GLP-1
receptor-mediated cellular targeting and intracellular delivery. This strategy
uses a covalently attached peptide carrier, the glucagon-like peptide-1
(GLP-1), that delivers estrogen selectively to specific tissues in order to
improve the therapeutic index of estrogen. Tissue specific delivery of estrogen
is limited to cells that co-express both estrogen as well as GLP-1 receptors. The
(GLP-1)-estrogen conjugates (Figure above, lower panel) that were <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013074910&recNum=51&docAn=US2012065492&queryString=(%20&" target="_blank"><span style="color: blue;">discovered</span></a> contain
plasma-stable linkages and are reported to exhibit improved sex-independent
efficacy over either of the individual hormones alone for the treatment of
diabetes and obesity. <o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In order to develop an orally
bioavailable treatment option for brain-selective estrogen therapy, an
alternate small-molecule strategy is desired. A research group led by <a href="http://www.hsc.unt.edu/prokai/" target="_blank"><span style="color: blue;">Laszlo Prokai</span></a> has initiated preclinical evaluation of a unique synthetic steroid that was designed for the treatment of estrogen-responsive central disorders. His
approach involves development of a ‘bioprecursor prodrug’ that undergoes
enzymatic bioactivation to 17<span style="font-family: "symbol";">b-</span>estradiol
(E<sub>2</sub>) by a reductive process catalyzed by an enzyme that is selectively
expressed in the brain. The specific bioprecursor, <a href="http://stm.sciencemag.org/content/7/297/297ra113" target="_blank"><span style="color: blue;">10<span style="font-family: "symbol";">b</span>,17<span style="font-family: "symbol";">b-</span>dihydroxyestra-1,4-dien-3-one</span></a>
(or DHED), unlike a conventional prodrug, does not contain any auxiliary promoieties
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through hydride transfer from the coenzyme NADPH (mechanism shown above, top
panel) to the C1 position of the A-ring dienone followed by elimination of
water to furnish E<sub>2</sub>. In vitro metabolism studies using tissue
homogenates indicated that DHED was converted to E<sub>2</sub> in the brain,
but not in peripheral tissues such as the uterus. In vivo experiments using
deuterated-DHED demonstrated that <i style="mso-bidi-font-style: normal;">d<sub>3</sub>-</i>E<sub>2</sub>
was produced exclusively in the brain. Estrogen was not detected in peripheral
tissues, nor was DHED detected in the brain. Oral, intravenous and subcutaneous
administration of the prodrug to ovariectomized rodents resulted in rapid,
brain-selective bioconversion to E<sub>2</sub>.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In order to evaluate DHED in a
preclinical model of an estrogen-responsive human CNS disorder, a Forced Swim
Test (FST) study was conducted. The <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353513/" target="_blank"><span style="color: blue;">Porsolt Forced Swim Test</span></a> is a widely accepted
animal model of the human condition of depression, used to screen for
antidepressant-like pharmacological activity. The test is centered on a
rodent’s response to the threat of drowning and the result of the test, a quantitation
of reduced behavioral immobility, is interpreted as measuring susceptibility to
negative mood. In an FST study, animals are subjected to two trials during
which they are forced to swim in a glass cylinder filled with water, from which
they cannot escape. The second trial is performed 24 hours after the first. The
time that the animal spends in the second trial without making movements beyond
those required to keep its head above water, referred to as immobility time, is
measured and is known to be decreased by antidepressant drugs. The FST is also
referred to as the “behavioral despair test.”</span><o:p></o:p></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhEFXJ_Lpe6NHgiorf6MbY_NckL_ND-UAnjf1ctlqJmL3diSw0bRuaB-kLIlDrgQWVYcGH28s6zoo01W_Yi7VCUQ-EB19atwn9RvFxJFh_jIMO1ObbVeXIF9rsNpOv_-sh-WklLmoG7bd3X/s1600/neuropharm.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="238" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhEFXJ_Lpe6NHgiorf6MbY_NckL_ND-UAnjf1ctlqJmL3diSw0bRuaB-kLIlDrgQWVYcGH28s6zoo01W_Yi7VCUQ-EB19atwn9RvFxJFh_jIMO1ObbVeXIF9rsNpOv_-sh-WklLmoG7bd3X/s640/neuropharm.jpg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Reproduced from: <i>Science Translational Medicine</i> <b>2015</b>, <i>7</i>, pp. 297ra113.</span></td></tr>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>When subcutaneously administered to
ovariectomized rodents at identical doses, DHED treatments engendered decreased
FST immobility times as compared to direct administration of E<sub>2</sub> (FST
data shown above, reproduced from <i style="text-align: center;">Science Translational Medicine</i><span style="text-align: center;"> </span><b style="text-align: center;">2015</b><span style="text-align: center;">, </span><i style="text-align: center;">7</i><span style="text-align: center;">, pp. 297ra113</span>). Importantly, co-injection of a
high-affinity estrogen receptor antagonist (<a href="http://www.tocris.com/dispprod.php?ItemId=2320#.VlJTmkvsHFI" target="_blank"><span style="color: blue;">ICI 182,780</span></a>, structure depicted
above) blocked the antidepressant-like effect in both treatment groups,
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unique bioprecursor prodrug holds promise as a potentially safe therapy to
alleviate hypoestrogenic depression resulting from surgical menopause. The
treatment should be devoid of adverse peripheral side effects associated with
the use of systemic estrogens. Moreover, the physicochemical properties of DHED,
such as lipophilicity and intrinsic aqueous solubility, are significantly
improved relative to the corresponding properties of 17<span style="font-family: "symbol";">b-</span>estradiol. The attractive biopharmaceutical properties of the
small-molecule DHED, in comparison to those of E<sub>2</sub> or estrogen-peptide
conjugates, could facilitate applications involving oral administration, which
is a much-coveted feature of a drug candidate.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>DHED is a synthetic molecule
obtained from <a href="http://www.sciencedirect.com/science/article/pii/0040403996006776" target="_blank"><span style="color: blue;">chemical oxidation</span></a> of estrogen derivatives. Upon exposure of an
estrogen to an initiator (benzoyl peroxide) and an oxidant (<i style="mso-bidi-font-style: normal;">m</i>CPBA) with simultaneous irradiation
from a 60-Watt light bulb, the A-ring phenol is converted to its corresponding <i style="mso-bidi-font-style: normal;">p-</i>quinol in moderate yield via the
radical mechanism depicted in the scheme above. It’s interesting to note that
subsequent treatment of quinols related to DHED with a strong Brönsted acid under thermally
forcing conditions promotes a fascinating skeletal <a href="http://www.cedricbrule.com/page.asp?rec=251&dossier=1" target="_blank"><span style="color: blue;">rearrangement</span></a> reaction that ultimately
yields an A-ring quinone through the intermediacy of its corresponding
hydroquinone. Estrane-type A-ring <i>p-</i>quinones have been reported to exhibit moderate cytotoxicity against certain cell lines. It remains to be seen as to whether or not this unique mode of
reactivity will preclude the use of DHED in applications involving intestinal
drug absorption from the gut, given that gastric pH is, of course, strongly acidic.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-26927023811016617802015-11-08T17:55:00.002-08:002015-11-15T07:14:09.497-08:00A Formal Synthesis of the Neem Limonoid Azadirachtin<!--[if gte mso 9]><xml>
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<span style="font-size: large;"> Azadirachtin exhibits potent
anti-feedant and growth-disruptant properties against a broad spectrum of
insects. In addition, its low mammalian toxicity has stimulated commercial
applications of formulated azadirachtin, obtained from Neem extract, as a safe
biopesticide. An oxidative rearrangement product derived from the limonoid
(tetranortriterpenoid) system, azadirachtin is an architecturally complex small
molecule. It contains 16 stereocenters, seven of which are tetrasubsituted
carbon atoms, along with an array of sensitive functionality including a
hemiacetal, tetrasubstituted epoxide and enol ether. In fact, azadirachtin is
so complex that it cannot be synthesized in meaningful quantities by chemists. The
single <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.200802675/abstract" target="_blank"><span style="color: blue;">disclosure</span></a> of a chemical synthesis of azadirachtin by the research group
of Steven Ley (Cambridge) relies on a “relay” strategy, required 22 years of
development time (and more than 35 workers) and proceeds in 0.00015% overall
yield. The Cambridge effort necessitated more than 70 synthetic operations with
a longest linear sequence of 48 steps. Recently, a second approach to
azadirachtin was <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201507935/abstract" target="_blank"><span style="color: blue;">reported</span></a> by <a href="http://park.itc.u-tokyo.ac.jp/org-chem/" target="_blank"><span style="color: blue;">Hidenori Watanabe’s laboratory</span></a> at The University
of Tokyo. Watanabe’s route, which is analyzed and discussed in some detail
below, intersects with an advanced intermediate that was produced during the
course of the Ley group’s pioneering relay synthesis. </span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Azadirachtin is comprised of western
decalin and eastern furo[<i style="mso-bidi-font-style: normal;">2,3b</i>]pyran
substructural fragments connected by a congested central C8-C14 linkage. In the
single completed synthesis of the natural product, the C8-C14 bond is forged by
an intermolecular alkylation/Claisen rearrangement sequence (diagrammed above). Very recently, Zhen
Yang’s research group (Shenzhen, China) has reported progress towards the
execution of a <a href="http://modernsteroid.blogspot.com/2015/09/recent-synthetic-work-on-triterpenoid.html" target="_blank"><span style="color: blue;">strategy</span></a> that will utilize a similar sigmatropic rearrangement reaction
to eventually connect the crowded vicinal quaternary carbon atoms at C8 and
C14. The new University of Tokyo approach to azadirachtin is conceptually
unique. Watanabe’s synthetic route features a novel intramolecular tandem
radical cyclization reaction that stitches together the B and E rings
simultaneously with the C8-C14 bond already in place. This post will highlight
their synthesis of an optically active eastern pyran segment as well as the
completion of an asymmetric formal synthesis of azadirachtin.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjrwOlKyqM5oYwDrybukRmkUFH5e7S7rPIpWRVLWFVGmvCHfGkcLqGYn5_8vn_NVYg9Gm43Oq_dWwQ7KtU0bxdaGzrkCbZgvfCk_8TzkHAhAbUerF-Lcq1prN5zXskWnKRhHwtr8ZTR0ifS/s1600/pyran.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="380" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjrwOlKyqM5oYwDrybukRmkUFH5e7S7rPIpWRVLWFVGmvCHfGkcLqGYn5_8vn_NVYg9Gm43Oq_dWwQ7KtU0bxdaGzrkCbZgvfCk_8TzkHAhAbUerF-Lcq1prN5zXskWnKRhHwtr8ZTR0ifS/s640/pyran.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Synthesis of the eastern pyran
system begins from an optically active monosubstituted cyclopentenone (structure
shown above) that is first elaborated to a carboxylic acid with additional diol
functionality protected as an acetal. The latent furo[<i style="mso-bidi-font-style: normal;">2,3b</i>]pyran system is next revealed by ozonolysis of the
cyclopentene moiety which, upon exposure of the initial oxidative cleavage
product to a Brönsted acid, furnishes the requisite oxacyclic system as a
mixture of four inseparable diastereomers. Subsequent silyl etherification of
the hydroxyl group allowed chromatographic separation of the stereoisomers and
the desired one was obtained in moderate (30%) yield. The lactone was then
partially reduced to a <span style="font-family: "symbol";">b-</span>oriented <i style="mso-bidi-font-style: normal;">O-</i>methyl acetal. Use of the <span style="font-family: "symbol";">b-</span>acetal in a subsequent epoxidation step was
previously demonstrated by Ley and co-workers to be synthetically advantageous.
The <span style="font-family: "symbol";">b-</span>acetal was elaborated to a methyl
ketone in six additional steps and subsequent nucleophilic addition of lithium
trimethylacetylide to the ketone delivered a tertiary alcohol with modest
stereoselectivity. Finally, a desilylated anomeric hydroxyl group was converted
to a phenylseleno moiety, intended to serve as a radical precursor in a later key
step, through the intermediacy of an anomeric mesylate. The overall route to
the furo[<i style="mso-bidi-font-style: normal;">2,3b</i>]pyran substructure
proceeds in 18 steps from the known cyclopentenone shown in the scheme above.
Synthesis of the complementary western spirocyclic carbaldehyde system (shown
below) was previously described by Watanabe and co-workers back in 2007 (highlighted <a href="http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201001218/abstract" target="_blank"><span style="color: blue;">here</span></a>).</span><o:p></o:p></div>
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgEbbrEXKK0yEE_KNtka0VuDylSogxt54pKB9tXf9717AcpvdgLo3Xc87vDCCW8lMVj66HiiuJZqoguCo811iWtSppTERXPlrphJlZC99HxP2GZ8vOuntv7O3BpVx6DkSwaZahlLMF2ufnI/s1600/fragment_assembly_rev.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgEbbrEXKK0yEE_KNtka0VuDylSogxt54pKB9tXf9717AcpvdgLo3Xc87vDCCW8lMVj66HiiuJZqoguCo811iWtSppTERXPlrphJlZC99HxP2GZ8vOuntv7O3BpVx6DkSwaZahlLMF2ufnI/s640/fragment_assembly_rev.jpg" width="506" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The two hemispheric fragments of
azadirachtin were joined by lithiation of the eastern terminal alkyne with
capture of the newly formed carbanion by the aldehyde substituent appended to
the western tetrahydrofuran ring system. This condensation reaction (depicted
in the scheme above) proceeds with full stereocontrol and an exceptional level
of efficiency, especially when one considers the complexity and functional
group tolerance of the transformation. The nucleophilic acetylide addition is
conducted successfully in the presence of an <span style="font-family: "symbol";">a,b-</span>unsaturated
lactone, two different acetals and a selenoether moiety. Moreover, the product
of the fragment union is a somewhat sensitive propargylic acetate that
serves as a latent allene system in a later stage of the synthetic route.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgr8Sb-FWozwdWsNohTcdfmYP1-W3dmexsYcPvOEiPYLBwSkT8INNDK-ouglyQiBk-xCwRA30AR8hpDgVc4B4vOH5ttath_hkeZYCJ0j5E-u9RSNohNuvHp6W3UlDqzflK1sa7_dXJd7wLf/s1600/endgame.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgr8Sb-FWozwdWsNohTcdfmYP1-W3dmexsYcPvOEiPYLBwSkT8INNDK-ouglyQiBk-xCwRA30AR8hpDgVc4B4vOH5ttath_hkeZYCJ0j5E-u9RSNohNuvHp6W3UlDqzflK1sa7_dXJd7wLf/s640/endgame.jpg" width="284" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The tetrasubstituted allene required
for the critical tandem radical polycyclization step is then installed by S<sub>N</sub>2'
addition of a methylcopper reagent to the aforementioned propargylic acetate to
provide requisite allene substrate as a single stereoisomer. All of the
previously noted comments about a high degree of functional group compatibility
equally apply to this challenging S<sub>N</sub>2' methylation as well. In the
highlighted transformation, heating of the allene in <i style="mso-bidi-font-style: normal;">N,N-</i>dimethylformamide
(DMF) under free-radical promoting conditions (<i style="mso-bidi-font-style: normal;"><sup>n</sup></i>Bu<sub>3</sub>SnH, AIBN) generates a carbon-centered
radical from the phenylseleno functionality. The transiently formed radical
engages the internal carbon atom of the allene in an addition reaction that simultaneously
establishes the eastern E-ring, along with a new tertiary C8 radical. The latter is
then poised to add into the proximal spirocyclic enone acceptor which assembles
the decalin B-ring and terminates the polycyclization cascade. The radical
cyclization product possesses the full carbon framework of azadirachtin, including
an intact C8-C14 bond and all of the appropriate functionality to complete the
synthesis of the limonoid natural product. Ten additional steps, post-radical
cyclization, were required to produce an intermediate that intersects with
Steven Ley’s synthetic process. Per the previously demonstrated Ley protocol,
nine additional steps are then required to elaborate the common advanced
intermediate into azadirachtin. In order to fully execute the new Watanabe
route, which encompasses the endgame of Ley, a longest linear sequence of 39
synthetic steps are required. Ley’s original route, while notoriously lengthy
and laborious (~71 total steps), required a longest linear sequence of 48
operations. Therefore, Watanabe’s new approach does not present a great deal of
improvement in step economy or overall efficiency. However, the new method for
construction of the azadirachtin skeleton provides an innovative solution to
‘the C8-C14 problem’ that has tormented synthetic chemists since the full
structure determination (revision) by Kraus in 1985. <o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The azadirachtin case study challenges
the reigning perception that ‘any molecule can be synthesized, given the
appropriate time and resources.’ This is actually the wrong metric by which to
judge the success of a synthetic project. At the end of a total synthesis
campaign, we should always ask ourselves, ‘how does this technology compare
with extraction from natural sources or microbial production by an optimized fermentation
process involving something like <a href="http://pubs.rsc.org/en/content/articlelanding/2015/cs/c5cs00025d" target="_blank"><span style="color: blue;">engineered biosynthesis</span></a>?’ Organic synthesis
should provide some advantage, if not with regard to efficiency of production,
then at least in terms of access to analogues with improved properties that
could not be obtained by a semisynthetic derivatization strategy.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com2tag:blogger.com,1999:blog-7873416017877082260.post-45403050828549073372015-10-22T18:42:00.002-07:002015-11-01T05:17:19.635-08:00The Sodium-Potassium Pump, “Neoglycosylation” and The Death of Emil Fischer<div class="separator" style="clear: both; text-align: justify;">
<span style="font-size: large;"> The effects of cardenolides and
related cardiotonic steroids on cardiac contractility is caused by a specific
interaction with the sodium-potassium pump (<a href="https://en.wikipedia.org/wiki/Na%2B/K%2B-ATPase" target="_blank"><span style="color: blue;">Na<sup>+</sup>,K<sup>+</sup>-ATPase</span></a>),
which maintains normal gradients of sodium and potassium across the plasma
membrane of eukaryotic cells. Partial inhibition of the ion-pumping function of
the enzyme leads to increased strength of myocardial muscle contraction and
this so-called positive inotropic pharmacological action is the basis of
digoxin’s clinical utility in the treatment of congestive heart failure. More
recently, the sodium-potassium pump has been shown to participate in
protein-protein interactions that stimulate growth-related signal transduction
pathways that are also essential to increased myocardial contractility. This Na<sup>+</sup>,K<sup>+</sup>-ATPase-induced
second messenger signaling is thought to have different downstream consequences
in various cell types (e.g. cancer versus non-malignant). Indeed, up-regulation
of the sodium-potassium pump has been observed in a variety of cancers
including ovarian, pancreatic and melanoma. This has led to the notion that
cardiotonic steroids, as inhibitors of the Na<sup>+</sup>,K<sup>+</sup>-ATPase
catalytic alpha subunit, represent viable lead compounds for the
chemotherapeutic treatment of cancer. In a small cohort of breast cancer
patients, it was reported that women who were taking a cardiotonic steroid at
the time of their breast cancer diagnosis had tumors with less aggressive phenotypes
than the breast tumors of women not taking a steroid such as digoxin. The same
authors later reported a higher recurrence rate of cancer among women not
taking a cardiotonic steroid drug. However, subsequent epidemiological studies
of the association between cardenolide use and breast cancer incidence gave
<a href="http://www.breast-cancer-research.com/content/pdf/bcr2205.pdf" target="_blank"><span style="color: blue;">conflicting</span></a> results. </span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjej1nukokKaTw9x9jnJasvTV7QKCAH58uh7WJseX59WEPAdiuXMAmp-2gzrenLHLePqyjMZeHKHFl9jeXIgUF4R09wqOueCN7D9ooRHc1HgW2VjBlrXD1cKifv_oLy_vp9WgUry0DK4E0_/s1600/ouabain_binding_site.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="324" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjej1nukokKaTw9x9jnJasvTV7QKCAH58uh7WJseX59WEPAdiuXMAmp-2gzrenLHLePqyjMZeHKHFl9jeXIgUF4R09wqOueCN7D9ooRHc1HgW2VjBlrXD1cKifv_oLy_vp9WgUry0DK4E0_/s640/ouabain_binding_site.jpg" width="640" /></a></div>
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<span style="font-size: large;"> Drug discovery research targeting
the Na<sup>+</sup>,K<sup>+</sup>-ATPase is now facilitated by the recently
reported <a href="http://www.pnas.org/content/110/27/10958.abstract" target="_blank"><span style="color: blue;">crystallographic studies</span></a> depicting the enzyme (from pig kidney) in
complex with ouabain and digoxin, extended to 3.4 angstrom-resolution. The
crystal structures clearly illustrate the extracellular region of the sodium-potassium
pump to which cardiotonic steroids bind. A relatively small set of amino acids
in the steroid-binding pocket serve as the primary contributors to binding the
sugar substructure of the ligand. Interestingly, a handful of mutations near
the binding site confer protection from poisons such as ouabain to a diverse
range of insects, amphibians, reptiles and mammals, illustrating that similar
selection pressures have resulted in <a href="http://www.pnas.org/content/112/38/11911.abstract" target="_blank"><span style="color: blue;">convergent evolution</span></a> across the animal
kingdom.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjQz6tsKohGkpgjmysAWe9iYuhr_awY8c5_khvkNHLLCYhNSOIduHaH5aBjuVb4bVIi3M7HW22cCKimfwRp5H1Q-D0lMOkBtHFhYvgx7Plz1JkPnC1tQ7RMpsMxLr3BdKYuCNxdl3IyKiuf/s1600/synthesis.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="526" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjQz6tsKohGkpgjmysAWe9iYuhr_awY8c5_khvkNHLLCYhNSOIduHaH5aBjuVb4bVIi3M7HW22cCKimfwRp5H1Q-D0lMOkBtHFhYvgx7Plz1JkPnC1tQ7RMpsMxLr3BdKYuCNxdl3IyKiuf/s640/synthesis.jpg" width="640" /></a></div>
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<span style="font-size: large;"> Based on its in vitro anticancer properties, and in conjunction with selected patient profiling data suggesting that the survival rate of cancer patients taking <i>digitalis</i>-derived drugs is statistically enhanced, digitoxin has been identified as a lead compound for oncology treatment applications. Jon Thorson’s research group at the University of Kentucky has used digitoxin as a model system for chemical derivatization by a technique that he refers to as ‘<a href="http://www.pnas.org/content/102/35/12305.full" target="_blank"><span style="color: blue;">neoglycorandomization</span></a>.’ The method applies a chemoselective glycosylation reaction <a href="http://www.sciencedirect.com/science/article/pii/S0040402098007637" target="_blank"><span style="color: blue;">developed</span></a> in the late 1990’s to derivatized terpenoid aglycone substrates to produce ‘glycodiverse’ libraries via a one-step divergent process. The protocol circumvents the need for protecting group strategies, selective anomeric activation and stereochemical control over carbohydrate coupling steps. The neoglycosylation reacton, itself, is a chemoselective glycosylation between an <i>N,O-</i>dialkylhydroxyamine (a nucleophilic alkoxyamine) and an unprotected reducing aldose (hemiacetal). The adduct that is formed between the reacting partners, a ‘neoglycoside,’ exists as a cyclized saccharide containing an intact N-O bond. <a href="http://pubs.acs.org/doi/10.1021/acsmedchemlett.5b00120" target="_blank"><span style="color: blue;">Recently</span></a>, Thorson and co-workers used the neoglycorandomization technique to probe the structure-activity relationships associated with the sugar/amine regiochemistry of a set of digitoxigenin neoglycosides. They quickly identified a 3-amino-substitution on the sugar to be most advantageous, affording a digitoxigenin monosaccaride derivative (structure depicted above) that is equipotent to digitoxin in an in vitro assay against the non-small lung cancer cell line A549. The authors rationalize the cytotoxicity data using a docking model of the sodium-potassium pump derived from human Na<sup>+</sup>,K<sup>+</sup>-ATPase ligand-bound crystal structures. In this case, molecular modeling revealed a correlation between the determined anticancer activity with ligand-binding site occupancies wherein the polar sugar/amine moiety is fully solvent-exposed.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgf4qM_MUrZKB9rWwZVH1pHLMy3kb4xzC1q74lS1n4RhzPKVwOVSJO9fwV4McqboHoOuO5AtcXjSzlIWRKwABaOJhK7NCq6luePYmyLeS8v4vyy0dDtm60v1fjyhDIBez89P5Rhi_iovSob/s1600/toxin_rev.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="348" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgf4qM_MUrZKB9rWwZVH1pHLMy3kb4xzC1q74lS1n4RhzPKVwOVSJO9fwV4McqboHoOuO5AtcXjSzlIWRKwABaOJhK7NCq6luePYmyLeS8v4vyy0dDtm60v1fjyhDIBez89P5Rhi_iovSob/s640/toxin_rev.jpg" width="640" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>It must be stated that when a
chemist conducts drug discovery research for a living, it is indoctrinated at a
relatively early stage of one’s career that molecules containing two consecutive heteroatoms linked by a sigma bond should not show up in screening libraries. So,
compounds that contain a heteroatom-heteroatom bond that is not part of a
heteroaryl ring system, for example hydrazides and oximes, are strongly
discouraged as lead generation starting points in spite of their synthetic
accessibility. When you talk to career medicinal chemists about why this should
be the case, they usually say something like, “Well that’s what killed Emil
Fischer.” For the record, Fischer’s death was <a href="https://en.wikipedia.org/wiki/Hermann_Emil_Fischer#Personal_life" target="_blank"><span style="color: blue;">actually</span></a> self-inflicted; but it
probably didn’t help that he was suffering from an excruciatingly painful case
of intestinal carcinoma that was likely caused by exposure to a molecule that
he discovered, phenylhydrazine (see structure above). More anecdotal evidence
along these lines lies in the mushroom-derived toxin, gyromitrin, a carcinogen
present in several members of the distinctive fungal genus <i style="mso-bidi-font-style: normal;">Gyromitra</i>. Gyromitrin is basically a pro-drug delivery system for
methylhydrazine. In the body, methylhydrazine reacts with pyridoxal 5-phosphate, the active
form of vitamin B6, to form a hydrazone, resulting in reduced production of
GABA which leads to neurological symptoms. Gyromitrin is also metabolized to reactive
nitrosamide intermediates that decompose to methyl radicals causing liver
necrosis. Because of examples like these, I’m not a great supporter of
‘neoglycorandomization’ as an approach to drug discovery in spite of its conciseness. The neoglycoside molecules that comprise a ‘glycodiverse’ library
all contain R<sub>1</sub>R<sub>2</sub>N-OMe functionality that seems like it
might not be an ideal starting point for drug discovery. Personally, I would
rather invest time and resources towards the additional effort required to synthesize a smaller,
more focused set of well-designed screening targets. Moreover, the bigger
problem with digitoxin and related cardiotonic steroids as chemotherapeutic lead
compounds is their notoriously low cytotoxic selectivity for human cancer cells
versus human non-malignant cells, which is typically not higher than ten-fold. To
this point, Thorson, in his recent <a href="http://pubs.acs.org/doi/10.1021/acsmedchemlett.5b00120" target="_blank"><span style="color: blue;">MedChem manuscript</span></a>, notes that the
aminosugars described in his study present opportunities for conjugation to cancer-targeting antibodies as a strategy to improve their
therapeutic window of efficacy and enable their application in the
chemotherapeutic treatment of cancer.</span><o:p></o:p></div>
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<br /></div>
<!--EndFragment-->BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-50657286265661931092015-10-11T14:47:00.000-07:002015-10-12T17:18:03.129-07:00New Cyclopentane-Based Sialyltranferase Inhibitors as Lead Compounds for the Chemotherapeutic Treatment of Cancer<!--[if gte mso 9]><xml>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Sialic acid-containing
glycoconjugate antigens play a critical role in a number of physiological and
pathological biochemical processes, including cell-cell adhesion, immune defense
and, importantly, tumor cell metastasis. <span style="color: blue;"><a href="https://en.wikipedia.org/wiki/Sialyltransferase" target="_blank"><span style="color: blue;">Sialyltransferase</span></a> </span>enzymes catalyze the
transfer of sialic acids to terminal non-reducing positions on growing
oligosaccharide chains of glycoconjugates. Sialyltransferases of all origins
and subtypes share the same donor substrate, cytidine monophosphate <i style="mso-bidi-font-style: normal;">N-</i>acetylneuraminic acid (CMP-Neu5Ac). The
enzyme-catalyzed transfer reaction is thought to proceed via an S<sub>N</sub>1-like
mechanism (outlined below) wherein partial dissociation of the cytosine
monophosphate leads to formation of a trigonal planar oxocarbenium species in
the transition state. Overexpression these enzymes and the consequent
overpresentation of sialylated antigens on cell surfaces are correlated with
poor prognosis in several different types of carcinomas. As such, the discovery
of cell-permeable inhibitors of sialyltransferase is considered a promising
strategy for antitumor drug development.</span><o:p></o:p></div>
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjMtsbrLSSbBnBZ-bIFuwFLYu9ScheLIAU9izx-1-zdny1ah1ZMwwAol4AivYg6hr6GUFtgJPSv8UuO8LvlEmJNkuLMhdOwZxK4PUB2VobqNhweqYlk754htZzRJ0MJ5EdHaG6HGeFmli_z/s1600/sialyltransferase.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjMtsbrLSSbBnBZ-bIFuwFLYu9ScheLIAU9izx-1-zdny1ah1ZMwwAol4AivYg6hr6GUFtgJPSv8UuO8LvlEmJNkuLMhdOwZxK4PUB2VobqNhweqYlk754htZzRJ0MJ5EdHaG6HGeFmli_z/s640/sialyltransferase.jpg" width="412" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/11394903" target="_blank"><span style="color: blue;">Soyasaponin I</span></a> is a glycosylated
pentacyclic triterpenoid natural product derived from soybean that displays
significant inhibition (K<sub>i </sub>= 210 nM) of a particular
sialyltransferase subtype. Related derivatives of the bile acid steroid
lithocholic acid were later <a href="http://pubs.rsc.org/en/content/articlelanding/2006/cc/b514915k/unauth#!divAbstract" target="_blank"><span style="color: blue;">developed</span></a> as potent inhibitors of a
sialyltransferase and one of those (Lith-<i style="mso-bidi-font-style: normal;">O-</i>Asp,
structure shown below) could effectively attenuate the total sialylation on
cancer cell surfaces and suppress tumor cell metastasis in <a href="http://cancerres.aacrjournals.org/content/71/2/473.long" target="_blank"><span style="color: blue;">in vivo</span></a> animal
models of cancer.<o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>However, the most potent
sialyltransferase inhibitors developed to date are structures that mimic the aforementioned
three-dimensional structure of the transition state of the enzymatic process (for a classic example of transition state analogue design, see <a href="http://pubs.acs.org/doi/abs/10.1021/jo00249a013" target="_blank"><span style="color: blue;">here</span></a>). A
potent transition-state analogue related to the CMP-Neu5Ac glycosyl donor was
first <a href="http://pubs.acs.org/doi/abs/10.1021/ja017370n" target="_blank"><span style="color: blue;">described</span></a> by Richard Schmidt’s group in 2002. More recently, Xin-Shan Ye’s
laboratory in Beijing, China has <a href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01181" target="_blank"><span style="color: blue;">reported</span></a> a series of highly substituted
cyclopentane-containing compounds (highlighted example shown below) that were
designed based on similar <a href="http://cdn.intechopen.com/pdfs-wm/41534.pdf" target="_blank"><span style="color: blue;">principles</span></a> of enzyme-binding. I’ve advocated <a href="http://benthamscience.com/journal/abstracts.php?journalID=coc&articleID=117263" target="_blank"><span style="color: blue;">elsewhere</span></a>
that the cyclopentane ring is an excellent scaffold for drug discovery. Ye’s
new cyclopentanoid phosponates, whose overall conformation (likely an
interconverting half-chair and envelope) effectively mimics the somewhat planar
character of the CMP-Neu5Ac-derived oxocarbenium ion in the enzyme transition
state, provide additional support for this arguably underutilized <a href="http://modernsteroid.blogspot.com/2014/04/consider-cyclopentane.html" target="_blank"><span style="color: blue;">MedChem concept</span></a>. The most potent
cyclopentane derivative was synthesized by a 20-step sequence of reactions and
displays outstanding inhibitory activity against recombinant human ST6Gal-I.
Detailed structure-activity relationships across the series are also reported.
This study further illustrates the utility of the cyclopentane motif as a
modular scaffold for medicinal chemistry development programs.</span><o:p></o:p></div>
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BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com4tag:blogger.com,1999:blog-7873416017877082260.post-82250815718456285012015-10-04T06:27:00.000-07:002015-10-04T06:27:02.689-07:00Neil deGrasse Tyson on Baseball<div class="separator" style="clear: both; text-align: center;">
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<br />BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-20067282384808183242015-10-03T18:18:00.001-07:002015-10-04T06:05:53.120-07:00Dionicio Siegel’s ‘Nonbiomimetic’ Polyene Cyclization Process Enables the Total Synthesis of Celastroid Pentacyclic Triterpenoids<div class="separator" style="clear: both; text-align: center;">
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The natural product celastrol
exhibits diverse biological properties including anti-inflammatory and
anti-cancer, as well as suppression of phenotypes associated with
neurodegenerative disorders. For example, the unique quinone methide
<a href="http://www.scripps.edu/baran/images/grpmtgpdf/Michaudel_Apr_13.pdf" target="_blank"><span style="color: blue;">triterpenoid</span></a> acts as a downregulator of mediators of anti-inflammatory
responses such as interleukin-1<span style="font-family: Symbol;">a</span>, TNF-<span style="font-family: Symbol;">a</span> and nuclear factor <span style="font-family: Symbol;">k</span>B (NF-<span style="font-family: Symbol;">k</span>B). It also
inhibits human prostate tumor growth and human glioma xenografts in mice.
Recently, celastrol was identified as an inhibitor of heat shock protein 90
(Hsp90), which is over-expressed in cancer cells and plays a role in activation
of certain pro-oncogenic signaling molecules. Celastrol is a
non-ATP-competitive inhibitor of Hsp90 and acts via a mechanism that likely
involves (in some as yet undefined fashion) conjugate addition of cysteine
residues within biological nucleophile[s] to the electrophilic quinone methide
substructure. In 2011, Richard Silverman’s laboratory at Northwestern
University <a href="http://pubs.acs.org/doi/abs/10.1021/ja208359a" target="_blank"><span style="color: blue;">demonstrated</span></a> that a range of soft nucleophiles add to the
pharmacophore of celastrol in a highly stereospecific fashion. It is
interesting to note that a related triterpene derivative, bardoxolone methyl
(or CDDO, structure shown above), also contains a reactive cyanoenone Michael
acceptor motif embedded in the western A-ring of its pentacyclic architecture.
Its ability to generate reversible Michael adducts with biological sulfur
nucleophiles is also speculated to be relevant to the molecular mechanism of
action of CDDO. Bardoxolone methyl is currently in phase III clinical trials
for the treatment of severe chronic kidney disease in type 2 diabetes mellitus
patients.</span><br />
<span style="font-size: large;"> The <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b06261" target="_blank"><span style="color: blue;">total synthesis of celastrol</span></a> was
recently reported by Dionicio Siegel’s laboratory at the University of Texas at
Austin. The ultimate success of Siegel’s synthetic approach to celastroid pentacyclic
triterpenoids hinged on a polyene cyclization reaction that is described by the
authors as ‘nonbiomimetic.’ Siegel and co-workers note that “biological polyene
cyclization leading to celastrol is exceedingly difficult to reproduce in the
laboratory due to a set of complex and energetically unfavorable methyl and
hydride shifts.” The UT Austin team references synthetic work targeting
alnusenone and friedelin, conducted in the late 1960’s and 70’s by <a href="http://modernsteroid.blogspot.com/2012/06/r-e-irelands-total-synthesis-of-racemic.html" target="_blank"><span style="color: blue;">Bob Ireland’s</span></a>
group. At this juncture, it may be instructive for readers to revisit the
enzyme-catalyzed <span style="font-family: Symbol;">p-</span>cation polyene
cyclization of oxidosqualene into the ornate pentacyclic carbon skeleton of <span style="font-family: Symbol;">b-</span>amyrin (detailed mechanism shown below) in
order to understand why Siegel chooses to characterize his own cyclization reaction
as ‘nonbiomimetic.’</span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Tsutomu Hoshino’s laboratory at
Niigata University in Japan has <a href="http://onlinelibrary.wiley.com/doi/10.1002/chem.201502389/abstract" target="_blank"><span style="color: blue;">shown</span></a> that oxidosqualene (and related unnatural
polyene substrates) must be correctly ‘folded’ into a
chair-chair-chair-boat-boat conformation in order to facilitate polycyclization
leading to the intact <span style="font-family: Symbol;">b-</span>amyrin
carbocyclic scaffold. Hoshino’s group conducted studies involving incubation of
synthetic derivatives of oxidosqualene in the presence of <span style="font-family: Symbol;">b-</span>amyrin synthase derived from the African
plant, <i style="mso-bidi-font-style: normal;">Euphorbia tirucalli</i>. They
demonstrated that the methyl group at carbon position 30 of oxidosqalene plays
an important role in binding to a hydrophobic recognition site of the enzyme,
leading to appropriate construction of the ordered architectural conformation
of the polyene substrate. Hoshino's studies suggest that a correct folding conformation of the polyene
strongly influences the success of the polycyclization cascade. Oxidosqualene
analogues that possess an intact Me-30 are more efficiently converted into
pentacyclic terpenoid systems as compared to those lacking a terminal <i style="mso-bidi-font-style: normal;">(Z)-</i>Me group. Substrates that do not
contain Me-30 generate far more abortive cyclization products. It is clear from
the enzymatic mechanism depicted above, as well as the Hoshino group’s recent
biosynthetic studies (outlined below), that the chemical polyene cyclization
process developed by Siegel and co-workers at UT Austin is indeed
‘nonbiomimetic.’</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The UT Austin total synthesis of
celastrol is initiated by execution of a two-directional approach starting from
2,3-dimethylbutadiene. In relatively short order, an advanced polyene-aldehyde
intermediate (structure depicted below) is obtained by an expedient sequence of
reactions featuring a tin-lithium exchange/alkylation to install the aromatic
moiety. <a href="http://www.columbia.edu/cu/chemistry/groups/synth-lit/NR/2008_08_29-SZheng-Stork.pdf" target="_blank"><span style="color: blue;">Stork</span></a>-enamine Robinson annulation with methyl vinyl ketone (MVK) was successfully
conducted on multigram scale to generate a critical cyclohexenone intermediate
and subsequent lithium aluminum hydride reduction furnished the polyene
cyclization substrate as an inconsequential diastereomeric mixture. Remarkably,
exposure of a dilute solution of the cyclohexenol intermediate to the Lewis
acid ferric chloride at low temperature promoted the stereocontrolled formation
of the desired pentacycle with useful efficiency, in light of the complexity of
the overall transformation. Siegel’s ‘nonbiomimetic’ polycyclization reaction
was demonstrated on 1-gram scale. The Jones reagent was then used to oxidize
the benzylic position located in the B-ring and subsequent selenoxide elimination
installed the requisite enone. Demethylation afforded the catechol natural
product wilforol A, which served as an intermediate that was suitable for
eventual conversion into celastrol and its corresponding methyl ester,
pristimerin. The total synthesis of racemic celastrol (obtained as a red-orange
solid) was achieved in a total of 31 linear operations, starting from
2,3-dimethylbutadiene. The work is extremely important because it provides
synthetic access to a medicinally relevant quinone methide triterpenoid that
could not be easily obtained by a more cost-effective semisynthetic approach.
For example, it is difficult to envision a method by which one might
oxidatively convert a readily available pentacyclic triterpenoid such as
oleanolic acid (the starting material for bardoxolone methyl) or <span style="font-family: Symbol;">b-</span>amyrin into a sensitive quinone methide
derivative. Hopefully, synthetic access to meaningful quantities of celastrol
will facilitate studies to elucidate the precise biochemical mode of action
leading to the diverse biological activies exhibited by this unique natural
product.</span><o:p></o:p></div>
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<span style="font-size: large;"><br /></span></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1tag:blogger.com,1999:blog-7873416017877082260.post-367719329294041822015-09-09T19:11:00.000-07:002015-09-10T16:48:42.983-07:00Recent Synthetic Work on the Triterpenoid Biopesticide Azadirachtin<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_OfxjP_5p-oTa_KkPgGKrtYNP_R88hotPzoj7Ew0DoCqeIMIOdI4ChRe6P5sS58AaGw9gOcPAS19-FENQqRveBPsuVuMNnfrxpcHCPWdPO2JfZ4wGyUrsNZQBym_TS6E-1FEd4GFTJnvC/s1600/NeemTree_fig.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="438" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_OfxjP_5p-oTa_KkPgGKrtYNP_R88hotPzoj7Ew0DoCqeIMIOdI4ChRe6P5sS58AaGw9gOcPAS19-FENQqRveBPsuVuMNnfrxpcHCPWdPO2JfZ4wGyUrsNZQBym_TS6E-1FEd4GFTJnvC/s640/NeemTree_fig.jpg" width="640" /></a></div>
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<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> Azadirachtin is a complex
tetranortriterpenoid limonoid natural product isolated from the neem tree <i style="mso-bidi-font-style: normal;">Azadirachta indica</i>, of the Meliaceae
family of flowering plants. The neem tree is evergreen and produces white and
fragrant flowers as well as a fruit that is smooth and olive-like. The neem is
native to India and the Indian subcontinent including Nepal, Pakistan,
Bangladesh and Sri Lanka. The azadirachtin content of neem oil pressed from
fruits and seeds varies from 300 to 2500 ppm, depending on the extraction
method and quality of the neem seeds used to produce the oil. Nimbin was the
first limonoid extracted from the neem tree. Subsequently, more than 150
bioactive chemical constituents were isolated from neem oil and various neem
tissues. Aside from triterpenoids, neem is known to contain sterols such as <span style="font-family: Symbol;">b-</span>sitosterol and stigmasterol, as well as
polyunsaturated fatty acids.</span><br />
<span style="font-size: large;"> Azadirachtin
is a powerful insect repellent/anti-feedant with low mammalian toxicity (LD<sub>50</sub>
in rats is >3.5 g/kg). A 1.2% formulated solution of azadirachtin is
marketed as Azatrol, an insecticide that provides broad-spectrum insect control
and is non-toxic to honeybees. Azadirachtin is the active ingredient in a
number of other pesticides including TreeAzin, AzaMax and AzaGuard. The
enormous commercial potential of new azadirachtin analogues as safe anti-insect
agents has inspired/funded organic chemists for decades. The sole chemical
synthesis of azadirachtin, reported in 2007 by Steven Ley’s group at the
University of Cambridge, relied on a relay approach and required >70
synthetic operations. Ley’s retrosynthetic disconnection of the crowded vicinal
quaternary carbon atoms located at the C8 and C14 positions, a tactic that was
adopted by numerous contemporary research groups (most notably, Nicolaou’s), generates
two advanced synthetic intermediates: a highly oxygenated western decalin
substructure and an eastern furopyran oxabicycle. Zhen Yang’s team in Shenzhen,
China has recently disclosed remarkably concise protocols for the chemical
synthesis of both of these fragments. A discussion of Yang’s synthetic studies
of the azadirachtin-type limonoids is provided below.</span><br />
<o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Upon preliminary examination of the
molecular architecture of azadirachtin, the structural relationship between
this oxidatively rearranged tetranortriterpenoid and more simplified C13<span style="font-family: Symbol;">a/</span>17-furyl-androstane limonoids is perhaps
not immediately intuitive (otherwise put, what does azadirachtin have to do
with a steroid?!). Identification of the genes and proteins involved in the neem
biosynthetic machinery is currently the subject of intense investigation due to
the impracticalities associated with commercial production of azadirachtin via
chemical synthesis. The prevailing biogenetic theory is that azadirachtin
arises from C-seco-limonoids derived from Norrish <span style="font-family: Symbol;">a-</span>cleavage of an oxidation product of azadirone or azadiradione.
So, yes, azadirachtin is likely a biosynthetic descendant of azadirone, which
bears an androstane/steroidal core carbon skeleton. Cyclization of a
cyclopentenol precursor (bracketed intermediate shown above) onto the heteroaryl
furan system likely forges the eastern, bridged hydroxyfuran acetal motif.
Evidence for this type of biogenetic pathway is found in the chemical
composition of neem oil, which is known to contain relatively high levels of
putative biosynthetic intermediates including azadirone, azadiradione, nimbin,
nimbidinin, salannin, salannol, along with trace amounts of other structurally
related limonoids. </span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Yang’s synthesis of azadirachtin’s
<a href="http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b00829" target="_blank"><span style="color: blue;">western A/B decalin</span></a> fragment begins from the spearmint oil-derived enantiomer
of carvone, which was converted in two steps into the substituted cyclohexene
derivative depicted in the Scheme above. This early-stage intermediate was subjected
to palladium-catalyzed oxyalkynylation, furnishing the requisite [6,5]-oxabicycle
in good yield under optimized conditions. The reaction is completely regio- and
diastereoselective, with the relative stereochemical outcome presumably
dictated by minimization of steric interactions between the methyl and vinyl
substituents. Subsequent ozonolysis of the propenyl group then delivers an
allylic acetate intermediate bearing an intact endocyclic olefin. This latter
reaction was developed in the early 1980s by Stuart Schreiber’s group, then at
Yale University. Schreiber showed that the intermediary carbonyl oxide derived
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1,3-addition of methanol to generate an <span style="font-family: Symbol;">a-</span>methoxy
hydroperoxide species. Upon acylation of the hydroperoxide in the presence of
base, a Criegee rearrangement involving alkyl migration (similar to the
Baeyer-Villiger mechanism) ensues to provide the acetate as an inconsequential
mixture of diastereomers. Seven additional operations were required to eventually
produce the critical 1,7-diyne that was designed to serve as the substrate for
a remarkable gold-catalyzed tandem cyclization reaction, described below.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The gold-catalyzed cascade reaction
proceeded under mild reaction conditions, generating the densely functionalized
<i style="mso-bidi-font-style: normal;">trans-</i>decalin product as a single
stereoisomer in 49% yield. This stereocontrolled alkyne metathesis-type
cyclization reaction forms two rings and two new stereocenters in a single
operation. The fully intact azadirachtin western decalin substructure was
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overall route to Yang’s decalin requires 20 total synthetic operations,
starting from <span style="font-family: Symbol;">(-)-</span>carvone. It should be
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operations.</span><o:p></o:p></div>
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<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Yang’s synthesis of the <a href="http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b00831" target="_blank"><span style="color: blue;">eastern furo[<i>2,3b</i>]pyran azadirachtin fragment</span></a>
relies on silylglyoxylate-based synthetic <a href="http://renaud.dcb.unibe.ch/group-meetings/journal-club/journal-club-2010/p2010_5.pdf" target="_blank"><span style="color: blue;">technology</span></a> developed by Jeff
Johnson’s group at UNC Chapel Hill. Yang’s recent limonoid work extends
Johnson’s methodology to accommodate the use of allylzinc bromide in place of
Reformatsky’s reagent in the diastereoselective three-component coupling process
(see Scheme above). The reaction proceeds by addition of the allylzinc reagent
to the silylglyoxylate benzyl ester, followed by [1,2]-Brook rearrangement to
afford a zinc-chelated enolate. The latter nucleophile approaches the <span style="font-family: Symbol;">b-</span>lactone coupling partner from its less
hindered convex side to furnish the condensation product with exquisite
1,4-stereoinduction. The remaining stages of the route involve initial <span style="font-family: Symbol;">g-</span>lactonization followed by ozonolysis of a
lactol intermediate to construct the oxabicyclic ring system. A
bis-TBS-protected furo[<i style="mso-bidi-font-style: normal;">2,3b</i>]pyran building block was prepared in a total of nine steps and a differentially protected system,
similar to Ley’s advanced intermediate, was generated in 15 steps. Those
familiar with the Ley group’s endgame know all too well that the completion of
azadirachtin from the advanced intermediates described above is far from trivial.
It will be interesting to see the extent to which Yang’s expedited syntheses of
the eastern and western fragments will enable methodological improvements in critical
aspects of the azadirachtin endgame strategy, such as construction of the
notoriously challenging C8-C14 bond which links the two substructural
hemispheres of the natural product.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com4tag:blogger.com,1999:blog-7873416017877082260.post-14178560355639886752015-08-23T16:50:00.000-07:002015-08-24T17:43:18.608-07:00Application of Catalytic Asymmetric Olefin Hydroamination to Estrone Conjugation<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUZFg4HR4I0tMecUftopv8Yl4HEz5J2m6e0y_YyQRk3DMszY6w157kCqmnhFDbKSwSTGTS02Vn0wBLMy0ADE03Q199ApzHeewNm_4rKRRpy0EbXjYgAydHv-hnt0L6oJxtdLyrJybxyvx-/s1600/figure.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="532" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUZFg4HR4I0tMecUftopv8Yl4HEz5J2m6e0y_YyQRk3DMszY6w157kCqmnhFDbKSwSTGTS02Vn0wBLMy0ADE03Q199ApzHeewNm_4rKRRpy0EbXjYgAydHv-hnt0L6oJxtdLyrJybxyvx-/s640/figure.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The synthesis of optically active <span style="font-family: Symbol;">a-</span>branched chiral aliphatic amines often
relies on enzymatic resolutions or stoichiometric auxiliaries, such as the
Davis/Ellman <a href="http://faculty.chemistry.harvard.edu/files/myers/files/15-ellman_auxiliary.pdf" target="_blank"><span style="color: blue;"><i style="mso-bidi-font-style: normal;">tert-</i>butylsulfinimine</span></a>. Fukuyama’s nosylate alkylation/de-sulfonylation sequence is another effective way to access secondary amines in a stereocontrolled
fashion and can also be used to construct medium-sized rings. However, the <a href="http://isites.harvard.edu/fs/docs/icb.topic208898.files/week_of_Dec_3rd/Fukuyama.NOSYL_Review.CC.2004.pdf" target="_blank"><span style="color: blue;">Fukuyama secondary amine</span></a> synthesis is a multistep approach requiring unproductive
protecting group manipulations to access chiral amines.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> Recently, Stephen Buchwald’s group has
developed a copper-catalyzed intermolecular hydroamination reaction that
effectively converts unactivated internal olefins (<a href="http://www.sciencemag.org/content/349/6243/62.abstract" target="_blank"><span style="color: blue;"><i>Science</i> <b>2015</b></span></a>) and styrenes (<a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b05446?journalCode=jacsat" target="_blank"><span style="color: blue;"><i>JACS</i> <b>2015</b></span></a>) into enantioenriched <span style="font-family: Symbol;">a-</span>branched amines.
The catalytic cycle of this powerful transformation is initiated by
enantiodetermining hydrocupration involving the addition of copper(I) hydride
across the double bond of the olefinic substrate. This furnishes a secondary
alkylcopper intermediate in an enantioselective fashion. The intermediary
organocopper compound is susceptible to a chain-walking mechanism consisting
of iterative <span style="font-family: Symbol;">b-</span>hydride
elimination/migratory insertion steps that lead to the formation of undesired
achiral by-products. This pathway is completely suppressed under the new
Buchwald conditions. Rather, electrophilic interception of the transiently
generated alkylcopper species with a customized hydroxylamine ester furnishes
the intended amine product with release of copper benzoate. The latter is
reconverted to ligated copper hydride by a stoichiometrically applied
hydrosilane reagent. The electronic properties of the amine transfer reagent used
in the process were optimized for electrophilic reactivity toward the secondary
alkylcopper intermediate and resistance against reductive N-O bond cleavage
upon exposure to hydrosilane. The axially-chiral ligand, DTBM-SEGPHOS
(structure shown above), is highly active for promoting hydrocupration, yet effectively
discerns between prochiral faces of a minimally differentiated olefin such as
2-butene. The method has been integrated into a cascade sequence that generates
optically active pyrrolidines in one step from readily available precursors.
The chemistry was also successfully demonstrated in the context of conjugation
of chemically complex API-type substrates. For example, a vinylarene prepared
in one step from Claritin (loratidine) could be coupled with an amine transfer
reagent derived from estrone benzyl ether to afford the conjugated steroidal adduct
(structure shown in the Scheme above) in good yield and with a high level of
stereocontrol. The new Buchwald protocol has enormous potential for future
pharmaceutical applications and provides and answer to the long-standing synthetic
challenge of forging nitrogen-carbon bonds from abundant alkene precursors and
amines.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-45460187078062574662015-08-17T18:34:00.000-07:002015-08-18T06:10:01.535-07:00The Sterol-Binding Fungicidal Mechanism of Action of Amphotericin B<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3xkGTRSj7u8CjtA0N6mHsVVMpCt8rhkFW8xJTB1nUzwgbfkk2VA100uctKQNOePwsmfJd3m2FjPkpHG8N3hLs3E0bZ3MPG4dSbIfFA0q5Ir7gqnxu8YnVeNX5Nc5TM1SatYKlyKuNy_C6/s1600/1_AmB_structure.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="334" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3xkGTRSj7u8CjtA0N6mHsVVMpCt8rhkFW8xJTB1nUzwgbfkk2VA100uctKQNOePwsmfJd3m2FjPkpHG8N3hLs3E0bZ3MPG4dSbIfFA0q5Ir7gqnxu8YnVeNX5Nc5TM1SatYKlyKuNy_C6/s640/1_AmB_structure.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span><a href="https://en.wikipedia.org/wiki/Amphotericin_B" target="_blank"><span style="color: blue;">Amphotericin B</span></a> (AmB) is a chemically
complex polyene-macrolide natural product that has been used continuously since
the 1960s as a last line of defense against systemic fungal infections.
Unfortunately, AmB is plagued by an extrememly narrow therapeutic index.
Indeed, because of the often dose-limiting toxicity of the antifungal drug,
mortality rates for systemic fungal infections still hover near 50%.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> Martin Burke’s laboratory at the
University of Illinois at Urbana-Champaign has taken a keen interest in the
fungicidal mode of action of AmB, which has managed to evade significant
microbial resistance for over 50 years. A better understanding of the precise
nature of AmB’s ‘resistance-refractory’ mechanism might lead to new antimicrobial
agents with reduced toxicity. The prevailing model used to interpret
biophysical studies of AmB’s role within living systems is the ‘artificial ion
channel model.’ According to this theory, AmB exists in the form of small ion
channel aggregates that are inserted into lipid bilayers with membrane
sterols oriented in between vertically-stacked molecules of AmB, arranged in a circular pore or cavity (see Figure
below, top left). The artificial channels are thought to permeabilize and ultimately kill cells. The ion channel model dictates that the strategic pathway to
improving therapeutic index is by achieving selective formation of ion channels
in yeast over human cells.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<o:p></o:p><br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEipr9uFwVVFmMfCSkiBzrzowxpK3rpCy4aVfInR9sRJbF0dB_Qay-ysXaYTPhDcK1cq41g2zJBzxV8T-v3SVjiRRj_AqMg5-qYplcpFQQiAblTIlt2anWXKFi4QrKlsyvw8K-wvSRcShFpJ/s1600/2_MOA_v2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="492" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEipr9uFwVVFmMfCSkiBzrzowxpK3rpCy4aVfInR9sRJbF0dB_Qay-ysXaYTPhDcK1cq41g2zJBzxV8T-v3SVjiRRj_AqMg5-qYplcpFQQiAblTIlt2anWXKFi4QrKlsyvw8K-wvSRcShFpJ/s640/2_MOA_v2.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Burke has recently <a href="http://www.nature.com/nchembio/journal/v10/n5/full/nchembio.1496.html" target="_blank"><span style="color: blue;">advanced</span></a> an alternate mechanistic scenario
to explain AmB's potent fungicidal properties. In the 'sterol sponge model' (Figure above,
top right), AmB forms large extramembranous aggregates that extract the
essential sterol <a href="https://en.wikipedia.org/wiki/Ergosterol" target="_blank"><span style="color: blue;">ergosterol</span></a> from phospholipid bilayers. The coincidental extraction
of membrane cholesterol (unselectively with ergosterol) might then be primarily
responsible the observed toxicity of AmB to human cells. This insight, if
proven correct, could guide the development of novel AmB derivatives with an improved
therapeutic index. With regard to evasion of resistance, AmB may simultaneously
disrupt all of the cellular processes that depend on membrane ergosterol.
Simultaneous mutation of all requisite fungal proteins in order to alleviate
the ergosterol dependence of the pathogenic organism is then improbable and,
hence, no significant resistance emerges.<o:p></o:p></span></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In 2014, Burke’s group presented
evidence from biophysical, cell-based experiments that uniformly supports the
new sterol sponge model. As such, an improvement in the relative binding
affinity of AmB aggregates for ergosterol over cholesterol was expected to translate
to antimicrobial agents with lower toxicity towards human cells. The Illinois
team approached this challenge by initially examining a recent crystal
structure of an AmB derivative that reveals an intramolecular salt bridge
between the C16 carboxylate and the C3’ ammonium moiety of AmB’s mycosamine
subunit (See AmB molecular structure, depicted above). They hypothesized that a
complex network of intramolecular noncovalent interactions, including the
aforementioned salt bridge, orients the mycosamine in a conformation that is
capable of forming an H-bond to the 3<span style="font-family: Symbol;">b-</span>hydroxyl
of both ergosterol and cholesterol (diagrammed below). The mycosamine
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high-resolution structure of the AmB aggregate (the functional ‘sponge’), with
and without bound sterol, would enable rational design of new synthetic
molecules. However, in its absence, a practical and highly modular semisynthetic
route to derivatize the ‘eastern’ mycosamine-bearing substructural framework of
AmB was sought. Newly generated analogs would then be evaluated for sterol
binding selectivity and correlation to selective toxicity to yeast.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyEgnNYb-Cr23k9j9qT_Nu5a6NxZqtirdnuU8KS_Ve0LouI0mV71nQn5nhElGJrKdYg5xI6xpXVlq9rlnGtbs6u4bFbkMVR_O5r3ZWXZeneMdS6vG70gOlCVxSX9OWF5ed1qDQN97XObwC/s1600/3_AmB_sterol.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="504" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyEgnNYb-Cr23k9j9qT_Nu5a6NxZqtirdnuU8KS_Ve0LouI0mV71nQn5nhElGJrKdYg5xI6xpXVlq9rlnGtbs6u4bFbkMVR_O5r3ZWXZeneMdS6vG70gOlCVxSX9OWF5ed1qDQN97XObwC/s640/3_AmB_sterol.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>A remarkably concise strategy for
AmB derivatization was <a href="http://www.nature.com/nchembio/journal/v11/n7/abs/nchembio.1821.html" target="_blank"><span style="color: blue;">developed</span></a> by Burke and co-workers. The route (shown
below) involves only three reaction ‘pots’ and requires one chromatographic
separation to produce pure material on gram-scale. The exceptionally mild
oxazolidinone ring-opening by amine nucleophiles is noteworthy. The facile
nature of this transformation, which introduces a new point of diversity for
SAR studies, likely reflects inherent ring-strain residing within the
trans-fused 6/5 heterocyclic ring system of the bracketed intermediate. The
tetrahydropyran methyl ketal of the penultimate species is converted into its
corresponding hemiacetal during the course of HPLC purification, which uses
aqueous formic acid in the mobile phase. An ultracentrifugation-based membrane
isolation assay indicated that the new C16-urea derivatives exhibit binding
selectivity for ergosterol over cholesterol. Moreover, the sterol binding
selectivity was generally associated with an improvement in therapeutic index,
as indicated by a comparison of the minimum inhibitory concentration (MIC) against
<i style="mso-bidi-font-style: normal;">S. cerevisiae</i> with the minimum
hemolytic concentration (MHC) determined against human red blood cells. This
project is a great example of a practical and well-executed organic chemistry
strategy, applied to a long-standing pharmacological problem with profound human
clinical implications. The emerging AmB mechanistic picture is an example of a
rarely encountered pharmacological phenomenon – that is, noncovalent binding
between a small molecule drug and an endogenous small molecule. The seemingly
‘resistance-refractory’ nature of this type of mechanism renders it a highly
desirable platform for pharmacological intervention aimed at anti-infective
drug development with low tox and evasion of resistance. The work also
illuminates to the ubiquity and essential nature of sterols such as cholesterol
and ergosterol to living systems within the cells of both humans as well as
pathogenic organisms.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
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<span style="font-size: large;"><br /></span></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com2tag:blogger.com,1999:blog-7873416017877082260.post-75305487067557790542015-08-07T18:05:00.000-07:002015-08-08T07:08:21.401-07:00Glycosylation Reactions Involving a High Degree of Chemical Complexity: Nicolaou’s Total Synthesis of Shishijimicin A<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgwiZIupvoJN6I_cnCFcqZ3A-KQBp-uyjAKYastvifYVbtSJAXDw8pzumfL9aFkA2ce7QAq4Aw-hETSE9yrWJL3Ahu_f1hUCqBbn2FvrsIFFD7jTtb84yvYIgfqBvHWBalZWrQuCjX7UKeI/s1600/glycos1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgwiZIupvoJN6I_cnCFcqZ3A-KQBp-uyjAKYastvifYVbtSJAXDw8pzumfL9aFkA2ce7QAq4Aw-hETSE9yrWJL3Ahu_f1hUCqBbn2FvrsIFFD7jTtb84yvYIgfqBvHWBalZWrQuCjX7UKeI/s640/glycos1.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Naturally occurring glycosylated
steroids and triterpenoids often exhibit pharmacological bioactivity superior
to that of their corresponding aglycones. Prominent examples include the
immunostimulatory adjuvant <a href="http://modernsteroid.blogspot.com/2012/09/david-gins-synthesis-of-investigational.html" target="_blank"><span style="color: blue;">QS-21-apiose</span></a> and the <a href="http://modernsteroid.blogspot.com/2012/02/chemical-synthesis-of-cardiotonic.html" target="_blank"><span style="color: blue;">cardiotonic glycoside</span></a> drug
<a href="https://en.wikipedia.org/wiki/Digoxin" target="_blank"><span style="color: blue;">digoxin</span></a>. Limonin glucoside, unlike its parent aglycone, limonin, is freely
water-soluble and has been shown to lower levels of circulating biomarkers of
chronic inflammatory diseases when administered orally in beverages. Moreover,
while limonin glucoside is almost tasteless, low concentrations of its aglycone
impart an extreme bitterness that is unacceptable to consumers.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"> A number of fully carbohydrate-based
polysaccharide drugs have been registered to date, but most of these active
pharmaceutical ingredients (APIs) originate from natural sources. Synthetic
oligosaccharides are rare, due to a reliance of carbohydrate synthesis on linear
strategies involving elaborate, orthogonal protecting group schemes and
cumbersome purifications. <a href="https://en.wikipedia.org/wiki/Fondaparinux" target="_blank"><span style="color: blue;">Fondaparinux</span></a> (molecular structure depicted below) is
a unique synthetic pentasaccharide API that was approved in 2001 for the
prevention of venous thromboembolism. It has been obtained from total synthesis
by a route that requires approximately 50 chemical steps. In view of the
examples noted above, it is not surprising that the development of efficient
and scalable chemical glycosylation protocols is of great interest to the
pharmaceutical industry.</span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Total synthesis studies targeting bioactive
natural products often stimulate the invention of novel bond-forming methodologies
that enable the eventual chemical synthesis of increasingly complex classes of
drug candidates. This important area of research also provides an arena to
evaluate the effectiveness of existing synthetic technologies, when applied in
the context of molecular architectures at the height of chemical complexity.
The endiyne antitumor antibiotics fall into this latter category. Natural
products from the endiyne class such as calicheamicin <span style="font-family: Symbol;">g</span><sub>1</sub> (structure shown below) exhibit exquisitely potent
cytotoxicity against cancer cell lines due to a fascinating mechanism of action
involving <a href="http://www.chem.wisc.edu/areas/organic/studsemin/erwin/bergman_files/v3_document.htm" target="_blank"><span style="color: blue;">Bergman cycloaromatization</span></a>. This phenomenon gives rise to a
1,4-benzenoid diradical that can abstract two hydrogens from DNA, causing
strand cleavage. Calicheamicin <span style="font-family: Symbol;">g</span><sub>1</sub>
serves as the ‘warhead’ or ‘payload’ that is conjugated to an antibody in the
approved antibody-drug conjugate (<a href="https://en.wikipedia.org/wiki/Antibody-drug_conjugate" target="_blank"><span style="color: blue;">ADC</span></a>), <a href="https://en.wikipedia.org/wiki/Gemtuzumab_ozogamicin" target="_blank"><span style="color: blue;">Mylotarg</span></a>. The advent of ADCs has
prompted renewed interest in high-potency cytotoxic agents that were previously
unsuitable for clinical applications due to severe side effects. Recently, the
total synthesis of a related endiyne natural product, <a href="http://pubs.acs.org/doi/abs/10.1021/jacs.5b05575" target="_blank"><span style="color: blue;">shishijimicin A</span></a>, was
reported by K. C. Nicolaou’s laboratory at Rice University in Houston, Texas.
The inarguably impressive synthesis reported by Nicolaou’s group employs a
challenging glycosylative coupling reaction between two highly elaborated
fragments that calls attention to a limitation of the classical <a href="https://en.wikipedia.org/wiki/Chemical_glycosylation" target="_blank"><span style="color: blue;">Schmidt</span></a>
trichloroacetimidate protocol. The daunting glycosylation chemistry outlined
below highlights the synthetic difficulties associated with endiyne production in the laboratory and underscores the need for new and robust oligosaccharide coupling
technologies.</span><o:p></o:p></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpgdlULgPLxPvS8kznlwliL9u1H9J1oRtzTtZcM0vUW_ARFTx6oudoqW1nFgugzYp6s2jxKUvSqgU9MffI0ZrfZezskbh4RMZTR89TjJmBdenl3kWMxhyphenhyphenbVdNNmyCG81NAoyNXklZ7yWCz/s1600/glycos2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpgdlULgPLxPvS8kznlwliL9u1H9J1oRtzTtZcM0vUW_ARFTx6oudoqW1nFgugzYp6s2jxKUvSqgU9MffI0ZrfZezskbh4RMZTR89TjJmBdenl3kWMxhyphenhyphenbVdNNmyCG81NAoyNXklZ7yWCz/s640/glycos2.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In the course of Nicolaou and
co-workers’ total synthesis of shishijimicin A, the two advanced intermediates,
a trichloroacetimidate glycosyl donor and a hydroxy-endiyne glycosyl acceptor (Scheme
below, lower panel), were prepared by a lengthy but reasonably efficient
synthetic sequence of reactions. The two fragments were subjected to a standard
variant of the Schmidt glycosylation reaction, wherein exposure to the Lewis
acid BF<sub>3</sub>-OEt<sub>2</sub> promotes formation of a transient oxonium species
derived from the glycosyl donor, ultimately furnishing the <span style="font-family: Symbol;">b-</span>glycoside adduct in a meager 26% yield. The
reaction was exemplified on 40-milligram scale. The authors attributed the low
yield to steric hindrance, although both coupling partners contain a diverse
array of functionality that could potentially engage in unproductive pathways
under Lewis acidic conditions. The condensation product was shown to be
suitable for subsequent conversion to the natural product. Shishijimicin A
is expected to serve as a uniquely powerful payload for ADC biomedical applications
due to its extremely potent antitumor properties (IC<sub>50</sub> = 0.48 pM
against leukemia cells). A similarly complex endiyne family member,
<a href="http://pubs.acs.org/doi/abs/10.1021/ja905397p" target="_blank"><span style="color: blue;">maduropeptin</span></a>, was synthesized by Masahiro Hirama’s group at Tohoku University
in Japan in 2009. In the case of maduropeptin, an embedded tertiary alcohol
serves as the glycosyl acceptor in the critical glycosylative fragment-coupling
step. A Schmidt glycosylation using 6.4 milligrams of the endiyne glycosyl
acceptor afforded 4.9 milligrams (40% yield) of the advanced maduropeptin
synthetic intermediate, as a mixture of two atropisomers. Hirama et al achieved
the first total synthesis and structure revision of the maduropeptin
chromophore. The chemical synthesis of endiyne targets residing at the frontier
of chemical complexity is instructive to organic chemists and generates
precious material for biochemical investigations and ADC-related conjugation
studies. However, the yields achieved in the requisite late-stage glycosylative
coupling steps clearly illustrate a need for further methodological refinement within
this important and medicinally relevant area of synthetic chemistry.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-cpH0L2NTEZ1780h1Zzv0qBUxTDt-o-XB4oFnmsAGVzLgK2nGkyGrQPEox_Zczv7JATXRF2X9W_hTwVpsX1XTTfC3t2sM5d1LGVTYLdiJOmxvrtaPUrIzX5rOtfySdm7HX-5_CtIRL_XR/s1600/glycos3.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="334" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-cpH0L2NTEZ1780h1Zzv0qBUxTDt-o-XB4oFnmsAGVzLgK2nGkyGrQPEox_Zczv7JATXRF2X9W_hTwVpsX1XTTfC3t2sM5d1LGVTYLdiJOmxvrtaPUrIzX5rOtfySdm7HX-5_CtIRL_XR/s640/glycos3.jpg" width="640" /></a></div>
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<span style="font-size: large;"><br /></span></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-40455879187827449472015-07-19T16:43:00.000-07:002015-07-19T16:57:42.506-07:00On Biosynthetic and Biomimetic Steroid Chemistry: The Polyene Cyclization Mechanism of Lanosterol<!--[if gte mso 9]><xml>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The biogenetic mechanism for the
formation of the 6-6-6-5 tetracyclic steroid lanosterol (outlined below), an
intermediate in the biosynthesis of cholesterol, has been studied by chemists for
over half a century. Enzyme crystallographic data, together with other
bioorganic and mutational studies, have yielded a biomolecular mechanism for
enzymatic triterpene cyclization starting from acyclic 2,3-oxidosqualene. The
mechanism involves initiation through protonation by a specific aspartic acid
residue. The polycyclization cascade then proceeds away from the catalytic
acid, with intermediates shielded by aromatic amino acid residues that line the
active site cavity with <span style="font-family: Symbol;">p-</span>electron-rich
faces. However, this biosynthetic conversion is incredibly complicated and many
of its precise details have not been fully resolved. One key question that has
remained unanswered until recently concerns the extent to which ring formation
is concerted with the initial protonation step. Earlier this year, in an effort
to sort out uncertainties associated with this complex mechanism, Ruibo Wu’s
group in Guangzhou, China, in collaboration with a team at Vanderbilt
University led by the theoretical computational chemist Andes Hess, successfully
<a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201501986/abstract" target="_blank"><span style="color: blue;">characterized</span></a> the cyclization of squalene oxide at the highest computational
level carried out to date. </span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The investigators used quantum
mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations to
construct the overall cyclization free-energy profile (reproduced below) for
this fascinating biosynthetic transformation. The study shows that the entirety
of the process (acyclic substrate <span style="font-family: Wingdings; mso-ascii-font-family: Cambria; mso-ascii-theme-font: minor-latin; mso-char-type: symbol; mso-hansi-font-family: Cambria; mso-hansi-theme-font: minor-latin; mso-symbol-font-family: Wingdings;"><span style="mso-char-type: symbol; mso-symbol-font-family: Wingdings;">à</span></span>
protosterol cation) entails two concerted, asynchonous reactions which proceed
through two metastable states (the A and B states) and one stable intermediate,
under oxidosqualene cyclase (OSC) enzyme catalysis. The overall cyclization can
be considered a carbocation migration and is exergonic by ~4.4 kcal/mol. The
rate-limiting step is the concerted formation of the A-ring, with opening of
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species that is subsequently converted to the tetracyclic protosterol cation (the
D state) by a ring expansion with concomitant (concerted) formation of the
D-ring. Importantly, all previous experimental mutagenic data is consistent
with the identified reaction mechanism.</span><o:p></o:p></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The 2015 computational mechanistic
study of Hess and Wu will no doubt inspire the synthetic enthusiasts among us
to reflect on the myriad of creative ways in which organic chemists have tried
to mimic the action of the enzyme OSC in a laboratory flask or reactor. This area
of so-called ‘biomimetic’ research was pioneered by W. S. Johnson at Stanford
University in the 1960’s and 70’s. Johnson’s efforts were later extended by
countless others. In his 1976 <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.197600091/abstract" target="_blank"><span style="color: blue;">Review Article</span></a> in <i style="mso-bidi-font-style: normal;">Angewandte Chemie</i>, Johnson elegantly summarizes the synthetic strategy:
“Certain polyenic substances having <i style="mso-bidi-font-style: normal;">trans</i>
olefinic bonds in a 1,5 relationship can be induced to undergo stereospecific,
non-enzymic, cationic cyclization to give polycyclic products with all-<i style="mso-bidi-font-style: normal;">trans</i> (“natural”) configuration. These
transformations appear to mimic in principle the biogenetic conversion of
squalene into polycyclic triterpenoids…” A highlight from Johnson’s impressive
body of research is a remarkably short synthesis of racemic progesterone, starting
from the cyclopentenol shown below. Cyclization under Brønsted acidic
conditions produces a crystalline tetracyclic product <i style="mso-bidi-font-style: normal;">in 71% yield</i>. Subsequent zonolysis followed by intramolecular aldol
condensation then furnishes synthetic progesterone. A related process (lower
panel below) was also conceived by Johnson to generate a valuable 11<span style="font-family: Symbol;">a-</span>substituted intermediate that intersects
with a known commercial route for the production of hydrocortisone acetate.
More recently, ‘biomimetic’ polyolefin carbocyclization has been
elegantly applied by E. J. Corey’s laboratory to the chemical synthesis of
complex limonoid steroidal systems (highlighted <a href="http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201001218/abstract" target="_blank"><span style="color: blue;">here</span></a>).</span><o:p></o:p></div>
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BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-24698642370074856102015-07-07T17:43:00.001-07:002015-07-07T18:28:37.676-07:00Aminosterols from the Dogfish Shark: The Discovery of the Allosteric Phosphatase Inhibitor, Trodusquemine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj9eH4PEP9cSX7l5INbtQEvljH7ohCQVSuslpEsc3z8G3MvJwWtsv5_Pe4k6ijkxMFvJH41HsWt1IHrypzEQZCQdcgVwo_ByA2IaEOC_y50OM_LmB6-9-5-qw0pcmeBGRpCCb70gRmNbHAo/s1600/structures.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="226" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj9eH4PEP9cSX7l5INbtQEvljH7ohCQVSuslpEsc3z8G3MvJwWtsv5_Pe4k6ijkxMFvJH41HsWt1IHrypzEQZCQdcgVwo_ByA2IaEOC_y50OM_LmB6-9-5-qw0pcmeBGRpCCb70gRmNbHAo/s640/structures.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In 1993, as part of an effort to
search for antibiotic host defense agents in the gut of various animals
including the dogfish shark (spiny dogfish) <i style="mso-bidi-font-style: normal;"><a href="https://en.wikipedia.org/wiki/Spiny_dogfish" target="_blank"><span style="color: blue;">Squalus acanthias</span></a></i>, the unique antimicrobial aminosterol <a href="http://www.pnas.org/content/90/4/1354.full.pdf" target="_blank"><span style="color: blue;">squalamine</span></a> (structure shown
above) was discovered. Squalamine is essentially the condensation adduct
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steroidal portion of the squalamine structure bears the <i style="mso-bidi-font-style: normal;">trans</i> configuration at the A/B ring junction and is additionally
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activity against fungi, protozoa, and both Gram-negative and Gram-positive
bacteria. The antimicrobial activity was attributed to squalamine’s ability to
modify membrane integrity by increasing permeability. Interestingly, it was
later shown that squalamine also possessed antiangiogenic and antitumor
properties and the molecule was eventually advanced to Phase II clinical trials
for the treatment of patients with advanced nonsmall cell lung cancer.</span><o:p></o:p></div>
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<!--EndFragment--></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Attempts to procure larger amounts
of squalamine from <i style="mso-bidi-font-style: normal;">Squalus acanthias</i>
resulted in the discovery and isolation of a related aminosterol MSI-1436, later dubbed
trodusquemine. Trodusquemine, as compared to squalamine, features an
invariant steroid skeleton but is conjugated at C3 to spermine (as opposed to <i style="mso-bidi-font-style: normal;">spermidine</i>), an elongated tetrabasic
polyamine. Rather unexpectedly, trodusquemine was found to induce profound
appetite suppression <i style="mso-bidi-font-style: normal;">in vivo</i> in
mammals (<i style="mso-bidi-font-style: normal;">For another example of a natural
appetite-suppressant steroid, see <a href="http://modernsteroid.blogspot.com/2014/05/chemical-synthesis-of-natural-appetite.html" target="_blank"><span style="color: blue;">here</span></a>).</i> As a result, it has been
speculated that trodusquemine is responsible for the sporadic feeding behavior
of the dogfish, which eats only once every two weeks. In vitro screening
against a panel of potential cellular targets revealed <a href="https://en.wikipedia.org/wiki/Protein_tyrosine_phosphatase" target="_blank"><span style="color: blue;">protein-tyrosine phosphatase</span></a> 1B (PTP1B) inhibitory activity in cell-free and cell-based assays.
PTP1B is a negative regulator of the effects of insulin and leptin signaling
through dephosphorylation of the insulin receptor (IR) and IR Substrate 1,
thereby inactivating the insulin pathway. Thus, inhibition of PTP1B maintains
the insulin and leptin pathways in active, phosphorylated states, which
triggers appetite suppression. Indeed, PTP1B expression and activity is
increased in obese and insulin-resistant humans and neuronal-specific PTP1B knockout
mice have markedly reduced weight.</span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgK6BOc9ic5t5t3sDclGgKHhT8L3M2M-VxFHfUPiIeCMz3Z3yh7llgCsPFJkUVFqE2THeTcU43k3t3wfRxaAX-Kh7jAeNC95MO7Bjp0Vyk208YrOwUdlhCamQw53DDyjtoNEiuaPerQWEjS/s1600/phosphatase_inhib.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgK6BOc9ic5t5t3sDclGgKHhT8L3M2M-VxFHfUPiIeCMz3Z3yh7llgCsPFJkUVFqE2THeTcU43k3t3wfRxaAX-Kh7jAeNC95MO7Bjp0Vyk208YrOwUdlhCamQw53DDyjtoNEiuaPerQWEjS/s640/phosphatase_inhib.jpg" width="620" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The inhibitory activity of
trodusquemine at the cellular target PTP1B is significant because it has been
notoriously challenging for medicinal chemists to develop effective small
molecule inhibitors targeting the active site of this enzyme. One problem is a
high degree of active site protein sequence homology, leading to difficulties
in achieving selectivity over other off-target phosphatases. Moreover, potent
active site tyrosine phosphatase inhibitors were designed to mimic
phosphotyrosine (see examples shown above). Consequently, the inhibitor ligands
that were developed were highly charged and thus had limited membrane
permeability and drug development potential. A known inhibitor of
striatal-enriched protein tyrosine phosphatase (or STEP), a potential
Alzheimer’s target, is <a href="http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001923" target="_blank"><span style="color: blue;">TC-2153</span></a>, a synthetic molecule that features a rarely
encountered heterocyclic ring comprised of five contiguously attached sulfur
atoms. Current interest in a structure like TC-2153 reinforces the point that
it has been historically difficult to find small molecule phosphatase
inhibitors with conventional ‘druglike’ substructures and physicochemical
properties. Trodusquemine avoids many of these pitfalls by binding to an
inhibitory <i style="mso-bidi-font-style: normal;">allosteric</i> site within an
intrinsically disordered segment of the C-terminal, noncatalytic region of
PTP1B. Many of the previous high-throughput screening campaigns conducted
against PTP1B used a recombinant, truncated form of the enzyme lacking this
C-terminal segment and, therefore, failed to identify selective <i style="mso-bidi-font-style: normal;">allosteric</i> inhibitors such as
trodusquemine. As a selective, non-competitive inhibitor of PT1B, trodusquemine
has tremendous potential as an anti-obesity and anti-diabetic therapeutic agent.
<span style="color: #262626; mso-bidi-font-family: Times;">The molecule has also been
shown to be able to cross the blood brain barrier (BBB), and thus may be
centrally active, opening a new range of potential indications.</span> <span style="color: #262626; mso-bidi-font-family: Times;">Trodusquemine has been well
tolerated in dose escalation and dose ranging clinical studies completed to
date in over 65 patients.</span></span><o:p></o:p></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZqwlbE9z2MREJcR-EgXExUNZCDK8i4r2UtK0Hliz-0qKb2BwXl3WuwMHASS2rfGdglgcImd5OswcgdSaaElycvYTW-6zbvOQXcWLIkfl-7b8JwpAW7fsMZng-NCeoGWvrHS-4CAxO_Mbc/s1600/synthesis.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="338" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZqwlbE9z2MREJcR-EgXExUNZCDK8i4r2UtK0Hliz-0qKb2BwXl3WuwMHASS2rfGdglgcImd5OswcgdSaaElycvYTW-6zbvOQXcWLIkfl-7b8JwpAW7fsMZng-NCeoGWvrHS-4CAxO_Mbc/s640/synthesis.jpg" width="640" /></a></div>
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The antimicrobial natural product
squalamine has been synthesized by processes starting from <span style="font-family: Symbol;">b-</span>stigmasterol, as well as chenodeoxycholic
acid (CDCA, see Scheme above). One interesting and critical transformation that
has been <a href="http://pubs.acs.org/doi/abs/10.1021/jo981344z?journalCode=joceah" target="_blank"><span style="color: blue;">utilized</span></a> to generate gram-quantities of squalamine is a regio- and
stereoselective reductive amination with a spermidine equivalent, wherein the distal
primary amine is masked as a non-nucleophilic nitrile. In this conversion, the
primary amine reacts preferentially over the internal secondary amine to
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hydrogenation must be conducted under acidic conditions (TFA) to avoid
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cyclic amidine impurity. In this example, the semisynthetic squalamine was
purified by HPLC and isolated as the trifluoroacetate salt with a final purity
of 97%. One presumes that a similar process is currently used to manufacture
the related clinical candidate, trodusquemine.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-32805051985473677022015-07-04T17:02:00.001-07:002015-07-05T10:33:39.205-07:00Dragmacidolide A, A New Oxysterol Metabolite from the Dragmacidon Genus of Marine Sponges<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-Q2oodKjX6q-lRAc1IqI7q5ecYqC-4a6eX0WgE3HTZM2TQUk4zbtituFrFh89DiXP088J49kcmjc5n8nP7gSsDOYoGeigVPUaxO0Y-OCV6LVXQlF9TbLDInh-k8x9vhzGEuFH68ozlnAd/s1600/dragmacidon.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="286" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-Q2oodKjX6q-lRAc1IqI7q5ecYqC-4a6eX0WgE3HTZM2TQUk4zbtituFrFh89DiXP088J49kcmjc5n8nP7gSsDOYoGeigVPUaxO0Y-OCV6LVXQlF9TbLDInh-k8x9vhzGEuFH68ozlnAd/s640/dragmacidon.jpg" width="640" /></a></div>
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<span style="font-size: large;"><b style="mso-bidi-font-weight: normal;"><span style="mso-tab-count: 1;"> </span></b>Deep-water
sponges of the <i style="mso-bidi-font-style: normal;">Dragmacidon</i> genus
typically yield structurally complex bis-indole alkaloid compounds such as
<a href="http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b00327" target="_blank"><span style="color: blue;">dragmacidins</span></a> D, E and F. Some <i style="mso-bidi-font-style: normal;">Dragmacidon</i>
alkaloids have been shown to be potent inhibitors of the serine/threonine
phosphatases PP1 and PP2A. In addition, the dragmacidins exhibit antiviral,
antibacterial and antifungal bioactivities, as well as cytotoxicity towards
various cancer cell lines. Very recently, a <i style="mso-bidi-font-style: normal;">Dragmacidon
australe</i> specimen, collected by SCUBA off the coast of the <a href="https://en.wikipedia.org/wiki/Whitsunday_Islands" target="_blank"><span style="color: blue;">Whitsunday Islands</span></a> in Queensland, Australia, was investigated to gain a better
understanding of the chemistry of this poorly investigated genus. Surprisingly,
a new steroidal secondary metabolite, <a href="http://www.sciencedirect.com/science/article/pii/S0040402015009849" target="_blank"><span style="color: blue;">dragmacidolide A</span></a>, was isolated and characterized using 1D/2D
NMR and MS data. The isolation of a steroid from this sponge genus is unusual
given that previous reports of <i style="mso-bidi-font-style: normal;">Dragmacidon</i>
metabolites were comprised exclusively of indole and <span style="font-family: Symbol;">b-</span>carboline alkaloids (with the unique exception of the
nucleoside, <a href="http://www.tandfonline.com/doi/abs/10.1080/14786419.2014.915828?queryID=%24%7BresultBean.queryID%7D&#preview" target="_blank"><span style="color: blue;">dragmacidoside</span></a>). At this time, it cannot be ruled out that a microbial symbiont could be responsible for the biosynthetic production of the oxysterol, within the microenvironment of the sponge.</span><o:p></o:p></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQ9gkOMGLmvuQoiN15duunY5UUyxXP8xdDH3P80B2DNjmbnz9qTNvQLHPmXdiXYdWL7liIpMdHo1DLpzvA1BmngQrh-eA8wM9R0sM398VkQeDJcA8cHC3onEm3OWISRzPPpXJKG1Yn16MX/s1600/structure.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="260" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQ9gkOMGLmvuQoiN15duunY5UUyxXP8xdDH3P80B2DNjmbnz9qTNvQLHPmXdiXYdWL7liIpMdHo1DLpzvA1BmngQrh-eA8wM9R0sM398VkQeDJcA8cHC3onEm3OWISRzPPpXJKG1Yn16MX/s640/structure.jpg" width="640" /></a></div>
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>In order to obtain a small sample of
dragmacidolide A, the methanol/dichloromethane extract of a freeze-dried and
ground specimen of sponge was subjected to RP-HPLC purification and analysis of
the purified fraction suggested the presence of a steroid. Unfortunately, the
relative configuration of C20 and C22 could not be assigned on the basis of the
2D NMR data. Both H21, as well as H20, showed ROESY cross-peaks to protons on
the angular methylene projecting from the C/D ring junction (H18), indicating
that free-rotation about the C17-C20 bond was operative. The C20 configuration
depicted in the structure shown above is based solely on analogy to the
stereogenic disposition of the <a href="http://modernsteroid.blogspot.com/2014/07/contemporary-methods-for.html" target="_blank"><span style="color: blue;">side chains</span></a> of other archetypal cholestane-type
steroids (e.g. lanosterol or <a href="http://modernsteroid.blogspot.com/2012/01/osw-1-antiproliferative-steroidal.html" target="_blank"><span style="color: blue;">OSW-1</span></a>). The limited availability from natural
sources and highly oxidized nature of the dragmacidolide A skeletal framework
makes it an ideal target for chemical synthesis. New synthetic technologies
that provide access to large quantities of molecules like dragmacidolide A are
likely to lead to the discovery of new biological targets and properties of
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210699/pdf/nihms327344.pdf" target="_blank"><span style="color: blue;">pharmacotherapeutic significance</span></a>. </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-70633180224025569832015-06-17T17:06:00.002-07:002015-06-17T17:52:17.532-07:00An Excellent Overview of the [Bio]Synthesis and Bioactivity of ent-Kaurene Diterpenoids<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnn8fHq9kpmzaAnzHsoqnnhUTZrBD7uedAMn11EMGcvJW7BQoBBr2Oy5q7ViP9wlZ4dNW1KcmzpteJiv9XrIQovTFR2LJJyNwK4kGOO8kIbjFVZi_AMsyWX7h4ZYhSaDmk66FmRPJSd9B1/s1600/1-s2.0-S0040402015008121-fx1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="142" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnn8fHq9kpmzaAnzHsoqnnhUTZrBD7uedAMn11EMGcvJW7BQoBBr2Oy5q7ViP9wlZ4dNW1KcmzpteJiv9XrIQovTFR2LJJyNwK4kGOO8kIbjFVZi_AMsyWX7h4ZYhSaDmk66FmRPJSd9B1/s640/1-s2.0-S0040402015008121-fx1.jpg" width="640" /></a></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>The <i style="mso-bidi-font-style: normal;">ent-</i>kaurene class of natural products are diterpenoids that are
formed as secondary metabolites in higher plants of the genus <i style="mso-bidi-font-style: normal;">Stevia</i> and <i style="mso-bidi-font-style: normal;">Isodon</i>. Steviol diterpenoids and glycosides thereof accumulate in
the leaves of <i style="mso-bidi-font-style: normal;">Stevia rabaudiana</i> at
high concentrations and the plant extracts are marketed as ‘Stevia,’ a natural
low-calorie sweetener. At this site, we’ve <a href="http://modernsteroid.blogspot.com/2013/10/barans-total-synthesis-of-racemic.html" target="_blank"><span style="color: blue;">discussed</span></a> Stevia’s prominent role in
a key plot point on the show <i style="mso-bidi-font-style: normal;">Breaking Bad</i>.
We’ve also <a href="http://modernsteroid.blogspot.com/2014/05/cafestol-complex-kaurene-diterpenoid.html" target="_blank"><span style="color: blue;">covered</span></a> synthetic aspects related to <a href="http://www.scs.illinois.edu/white/pubs/pub29.pdf" target="_blank"><span style="color: blue;">cafestol</span></a>, an <i style="mso-bidi-font-style: normal;">ent-</i>kaurene diterpenoid found in coffee
drinks. Now Corinna Schindler’s group at the University of Michigan has
contributed an outstanding <a href="http://www.sciencedirect.com/science/article/pii/S0040402015008121" target="_blank"><span style="color: blue;">Review Article</span></a> in the journal <i style="mso-bidi-font-style: normal;">Tetrahedron</i> that presents an authoritative overview of <i style="mso-bidi-font-style: normal;">ent-</i>kaurene isolation, biosynthesis,
antibacterial and antitumor activity. The manuscript also provides a
comprehensive account of synthetic strategies (dating back to <a href="http://www.orgsyn.org/content/pdfs/obits/Ireland.pdf" target="_blank"><span style="color: blue;">Bob Ireland’s</span></a>
work in 1966!) used access <i style="mso-bidi-font-style: normal;">ent-</i>kaurene
diterpenoids in a laboratory setting. Prior to reading this Review, I’ll admit
that I was not aware of (and could not find in the scientific literature…not
for a lack of searching) the reason for adding the ‘<i style="mso-bidi-font-style: normal;">ent-</i>’ prefix to the ‘<i style="mso-bidi-font-style: normal;">ent-</i>kaurene’
natural products. Schindler et al clear that up in two sentences: <o:p></o:p></span></div>
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<br /></div>
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<i style="mso-bidi-font-style: normal;"><span style="font-size: large;">“In 1999, kaurene was classified as the
fundamental parent structure of this subclass of diterpenoids by the IUPAC.
Despite this nomenclature, the vast majority of kaurene diterpenoids isolated
to date belong to the ent-kaurenes, in which all asymmetric centers undergo
configurational inversion…”<o:p></o:p></span></i></div>
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<span style="font-size: large;">Thanks!</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com0tag:blogger.com,1999:blog-7873416017877082260.post-77439400807653123982015-06-14T12:41:00.001-07:002015-06-14T12:58:09.302-07:00Secosterols as Chemical Defense Weapons Derived from Marine Invertebrates<div class="separator" style="clear: both; text-align: center;">
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<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Certain benthic marine organisms
have served as an abundant source of architecturally diverse secondary
metabolites for natural products chemists. Structural classes derived from
<a href="http://pubs.rsc.org/en/content/articlelanding/2015/np/c4np00144c#!divAbstract" target="_blank"><span style="color: blue;">marine sources</span></a> include various types of peptides, neurotoxic alkaloids and
<a href="http://www.sibran.ru/upload/iblock/bef/bef0d5aa0850367af50fcf900a156541.pdf" target="_blank"><span style="color: blue;">halogenated sesquiterpenes</span></a>, to name a few. The most common explanation for this
phenomenon of <a href="http://pubs.rsc.org/en/content/articlelanding/2014/np/c4np00017j#!divAbstract" target="_blank"><span style="color: blue;">chemical ecology</span></a> is that marine invertebrates such as mollusks
and sponges, which are shell-less and have soft, unprotected body tissues, rely
on chemical defense substances to deter potential predators. Other postulated
roles for co-occurring chemical defense molecules include prevention of
fouling, inhibition of overgrowth and protection from ultraviolet radiation. An
alternate hypothesis is that some secondary metabolites serve no function at
all and are simply representative of accumulations of enzymatic side products
or have served as deterrents toward ancient predators that have since gone
extinct. Regardless, marine invertebrates have provided a vast supply of
bioactive molecules for the eventual <a href="http://www.nature.com/nrd/journal/v8/n1/full/nrd2487.html" target="_blank"><span style="color: blue;">discovery and development</span></a> of new
pharmacological tools and therapeutic agents.<o:p></o:p></span></div>
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<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-size: large;"><span style="mso-tab-count: 1;"> </span>Recently, in the journal <i style="mso-bidi-font-style: normal;">Angewandte Chemie International Edition</i>
(<i style="mso-bidi-font-style: normal;">ACIE</i>), Hideo Kigoshi and co-workers
reported the structural assignment of a new ‘seco-’ (defined as
ring-fragmented) steroid, isolated from a type of marine gastropod mollusk
commonly referred to as a ‘sea hare.’ Interestingly, certain sea hares are known
for the unique <a href="http://io9.com/sea-hare-ink-is-one-of-natures-most-unusual-bioweapons-461246802" target="_blank"><span style="color: blue;">ability to discharge a colorful, sticky ink</span></a> when threatened.
The defensive ink’s chemical composition induces <a href="http://blogs.goucher.edu/ckicklighter/files/2008/08/kicklighter-et-al-2005.pdf" target="_blank"><span style="color: blue;">sensory inactivation</span></a> in
predators such as spiny lobsters. Kigoshi’s team at the University of Tsukuba in
Japan disclosed the chemical structure of <a href="http://onlinelibrary.wiley.com/doi/10.1002/anie.201501749/abstract" target="_blank"><span style="color: blue;">aplysiasecosterol A</span></a> (see Table above,
top panel), a 9,11-secosteroid isolated from the marine sea hare <i style="mso-bidi-font-style: normal;">Aplysia kurodai</i>. The tricyclic <span style="font-family: Symbol;">g-</span>diketone skeletal framework of
aplysiasecosterol A is unprecedented and a compelling biosynthetic pathway starting
from a derivative of cholesterol was proposed by the authors. The new degraded
steroid exhibits modest cytotoxicity against the human myelomonocytic leukemia
cell line HL-60 (IC<sub>50</sub> = 16 uM). The eastern substructure of
aplysiasecosterol A, encompassed by the characteristic steroid D-ring and <a href="http://modernsteroid.blogspot.com/2014/07/contemporary-methods-for.html" target="_blank">c<span style="color: blue;">holestane-type side chain</span></a>, is reminiscent of the long-known polyhydroxylated
sponge-derived 9,11-secosterol, <a href="http://pubs.acs.org/doi/abs/10.1021/jo00224a023" target="_blank"><span style="color: blue;">herbasterol</span></a>. The fascinating and ornate structure
of herbasterol was characterized in 1985 by Capon and Faulkner (Scripps
Institute of Oceanography) and, to my knowledge, has never been synthesized by
chemical means. Aplykurodinone-1 is another marine secosteroid that has
generated intense interest (for a leading reference, see <a href="http://pubs.acs.org/doi/abs/10.1021/jo501684k" target="_blank"><span style="color: blue;">here</span></a>) amongst synthetic chemists, dating back to its
prominent inaugural <a href="http://renaud.dcb.unibe.ch/group-meetings/journal-club/journal-club-2010/p2010_29.pdf" target="_blank"><span style="color: blue;">total synthesis</span></a> in 2010 by Sam Danishefsky’s
group. Aplykurodinone-1 was isolated from the sea hare <i style="mso-bidi-font-style: normal;">Syphonota geographica</i> from the Mediterranean Sea off the Greek
coast and can be broadly classified as an oxidatively degraded steroid with
cytotoxic bioactivity against a range of human cancer cell lines. The related aplykurodins
(Table above, bottom panel) are a group of ichthyotoxic lactones that were isolated from
marine mollusks of the genus <i style="mso-bidi-font-style: normal;">Aplysia</i>
in the late 1980s to early ‘90s. Additional biochemical screening efforts will
likely uncover new pharmacological properties and cellular targets for marine
secosterols that may be pertinent to drug discovery programs.</span><o:p></o:p></div>
BHHhttp://www.blogger.com/profile/17674787259534472941noreply@blogger.com1