modern steroid science
Driven 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.
Wednesday, December 21, 2016
Sunday, January 31, 2016
On the Existence of Human Pheromones
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 Masters of Sex. IFF was (and continues to be) 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.
Pheromones were first described 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 human 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 androsta-4,16-dien-3-one and estratetraenol
(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.
A 2014 study 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 2013 investigation 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.’
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 D16,17 double bond within the steroidal D-ring.
It’s interesting to compare the
structure of 5a-androst-16-en-3-one to
the odorous macrocyclic ketone, civetone. Civetone is a known pheromone derived
from African civet 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.’ Androstenone happens to be the
active ingredient in a commercial product called BoarmateTM, which,
as one might gather from its name, was developed to assist farmers with swine
breeding.
In vertebrates, odors are sensed by
members of a family of seven-transmembrane G-protein-coupled receptors called
odorant or olfactory receptors (ORs) that are localized on the terminal knobs of
olfactory sensory neurons (see Diagram below). The human receptor OR7D4 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
that ultimately leads to the nerve cell signal. Interestingly, perceptual
variation in the intensity and pleasantness of certain odors has been shown to
be dependent on the OR7D4 gene variant that an individual carries. The OR7D4
genotype also predicts 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.
Sunday, January 17, 2016
Partial Synthesis of Linckosides A and B, Unique C8-Hydroxylated Steroids from the Okinawan Blue Starfish
Linckia
laevigata (also known as the Okinawan blue sea starfish) 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 L. laevigata 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 autotomy, 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, L.
laevigata 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.
In light of the regenerative
capacities mentioned above, natural products obtained from L. laevigata were screened in the early 2000s for much sought-after
neuritogenic pharmacological properties. Neuritogenic compounds or neurotrophic
factors, exemplified by nerve growth factor (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, see. 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 commonly encountered 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 linckosides A and B. 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.
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 b-thioarylether intermediate to an
oxaziridine reagent furnished the corresponding sulfoxide as an epimeric
mixture. Subsequent treatment with a mild base at 80 oC promoted cis-elimination of the sulfoxide to
yield a 5,7-diene. The D7,8
unit of unsaturation within the diene system is crucial to the overall strategy
to ultimately hydroxylate the embedded C8 position. However, the more
accessible D5,6 olefin was
first selectively epoxidized using methyltrioxorhenium and urea-hydrogen
peroxide and hydrolysis of the resultant oxirane generated the advanced 5a,6b-diol
intermediate shown above.
The Mukaiyama hydration reaction was
used to install the C8-hydroxyl group onto the steroidal skeleton of the critical
polyhydroxylated D7,8 olefin
intermediate. A similarly impressive cobalt-catalyzed Mukaiyama hydration
reaction was previously employed by Baran’s group for the stereocontrolled
functionalization of a trisubstituted D4,5
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 b-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 p-face of the olefin with Markovnikov selectivity. The reaction
was demonstrated on 330-milligram scale.
Yu’s group appended the final
monosaccharide unit to the western C3-hydroxyl using an o-alkynylbenzoate building block as the glycosyl donor. This type
of donor, which was developed in Biao Yu’s laboratory, is activated in the
presence of a gold(I) cationic catalyst and, in this example, the 2-deoxy-b-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.
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