Limonoid natural products have been
reported to possess a wide range of biological activities including
antimalarial, anti-HIV and, most notably, insect antifeedant. Phragmalin limonoids are oxidatively modified B,D-seco limonoids
that are biosynthetically derived from their relatively less oxidized progenitors,
the mexicanolides (representative structures depicted above). The architectural
relationship between the carbon skeletons of typical limonoids, mexicanolides
and phragmalins has been a previous topic of discussion at this site (here and
here). Another very good introduction to synthetic aspects related to the
limonoid molecular framework is this Scripps presentation. In brief,
mexicanolides possess an A/B-bicyclo[3.3.1]-ring system while phragmalin
limonoids contain an additional 1,8,9-orthoester functionality (two hydroxyls
condensed with an O-acetyl carbonyl
group) across the bottom (a-) face of
the B-ring. The phragmalin western A/B substructural domain is referred to as a
tricyclo[3.3.1.1]decane due to the additional bridging oxidative functionality.
Phragmalin limonoids are found only in the genera of the Meliaceae family of
flowering trees and shrubs. Libiguin A is a phragmalin-type B,D-seco limonoid
isolated from the Madagascarian meliaceae species, Neobeguea mahafalensis. The major structural difference between
phragmalin and libiguin A (highlighted above in blue) is the location of the
eastern lactone ring. The 17-oxo functionality, which is cyclized into the
lactone ring of phragmalin, is oxidized to a ketone in libiguin A. For this
reason, trans-lactonization of
phragmalin was explored as a practical semisynthetic approach (see below) to
provide access to quantities of libiguin A that will facilitate investigation
of the pharmacological properties of this new limonoid, as well as the biochemical
mechanism(s) of action that underlie its bioactivity.
The laboratory
of Jarl Wikberg at Uppsala University in Sweden discovered that libiguin A, extracted
and purified from natural sources, induces a profound stimulation of sexual
behavior in rodents at dosage levels in the low ug/kg
range. A subset of representative data from Wikberg and co-workers’ 2014 Planta Medica report is reproduced
above. The bar graph depicts rodent mounting behavior corresponding to the
different subcutaneous doses of libiguin A, indicated in mg/kg. The data set
actually describes the number of ‘mounts’ observed during the third hour after introduction of the
female to the male mouse. The normal pattern of rodent ‘mounting’ is that
initially the mounting activity is very high but then almost totally ceases
during the third hour. By contrast, libiguin A elicited dose-dependent and
sustained sexual activity over a long period of time after the introduction of
the mating partner to the male. The authors note that a central mechanism of
action is likely, in view of the unique behavioral patterns induced.
Curiously,
another complex steroid found in plant species such as the Tribulus and Dioscorea
families, namely protodioscin (molecular structure depicted above), is reported to elicit
sexual-enhancing ‘aphrodisiac’ effects. Protodioscin most likely exerts its
‘proerectile’/aphrodisiac effects because it is metabolized to bioactive
androgenic steroids such as [dihydro]testosterone and dehydroepiandrosterone.
Protodioscin has also been demonstrated to trigger the release of nitric oxide
in corpus cavernosum tissue. Regrettably, studies in humans involving this
intriguing plant-derived steroidal saponin have failed to show efficacy.
Isolation of
libiguin A from N. mahafalensis is
plagued by low natural abundance as well as the presence of many related
compounds with similar chromatographic properties. In order to obtain
sufficient quantities for the detailed biochemical characterization of the
sexual enhancing effects of the natural product, a semisynthetic process to
generate libiguin-type molecules was developed by Wikberg’s laboratory. Phragmalin
was identified as a raw material for the semisynthesis of libiguin A due to its
availability in large quantities from commercially cultivated species of the
Meliaceae family. For example, phragmalin can be obtained from seeds of Chukrasia tabularis at a yield of 3.52
g/kg of seeds. Access to gram-quantities of this complex limonoid allowed
Wikberg and co-workers to explore the critical trans-lactonization transformation required to construct the
skeletal connectivity of the libiguins. First, a selective monoacylation of the
C3-hydroxyl of phragmalin with isobutyryl chloride afforded intermediate 1. Next, reaction of
the lactone 1 with MeONHMe-HCl promoted by trimethylaluminum accomplished the
desired lactone ring opening. The authors note that a number of alternate
hydrolytic, reductive and aminolytic conditions met with limited success. The effectiveness
of the Weinreb amidation relied on careful time control in order to avoid the
formation of unwanted by-products derived from ester aminolysis. The unblocked C17-hydroxyl
group could then be selectively oxidized to the requisite ketone using
Dess-Martin periodinane. In the penultimate step, lactone ring closure with the
C30-hydroxyl was achieved upon exposure of the advanced intermediate 3 to the
Lewis acid, TMSOTf. Finally, acylation of the remaining C2-hydroxyl, again
under Lewis acidic conditions, secured semisynthetic libiguin A in excellent
yield. In spite of its demonstration on relatively small scale (8 mg of
libiguin A were synthesized), the route will allow the authors to conduct more
advanced pharmacological profiling of the natural product, as well as analogues,
in order to better characterize the biochemical origins of the sexual
stimulating activities that were previously observed.
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1-Cinnamoyltrichilinin is a limonoid isolated from the fruits of Melia toosendan with antibacterial activity. 1-Cinnamoyltrichilinin
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