A SHORT PRESENTATION Jan 2012 Histrionicotoxin from South American poison-dart frogs
In 1823, a western traveller by the name of Captain Charles Stuart Cochrane reportedon his expeditions around the lowland tropical rain forests of Colombia. Heencountered tribes of native Indians who used poison arrows and blowgun darts forhunting.Eventually, He discovered that the poison had been been extracted from smallbrightly coloured frogs.One of these poisons is called histrionicotoxin, named after the subspecies fromwhich it is extracted, Dendrobates histrionicus.
Histrionicotoxins are a group of related toxins found in the skin of poison frogs from theDendrobatidae family, notably Dendrobates histrionicus.It is likely that as with other poison frog alkaloids, histrionicotoxins are not manufactured by the amphibians, but absorbed from insects in their diet and stored in glands in their skin.Histrionicotoxin is a poison excreted by frogs.In order to extract this poison from frogs, the frog is often tortured in a way that itperspires more than normal and causes it to release a white foam on its back.The frogs can be found in the lowland tropical rain forests or in themountains, mostly in South and Central America.Histrionicotoxin has also been used to preserve arrows.In the 1800s, tribes of native Indians used it to cover their arrows and blowgundarts with the compound when they went hunting.
The frogs which Cochrane wrote aboutbelong to any one of thefamilies Dendrobates,Phyllobates, Atropophrynus and Colostethus, and are characterisedby their highly coloured markings, whichadvertise the poisonous nature of thesecreatures in an attempt to warn offpredators. Their habitat ranges from thelowland tropical rainforests to aridmountain areas and are generally confinedto South and Central America. Some speciesare found next to rivers and streams or indamp shaded areas, whereas others spendtheir time in trees or even in dry opencountry, provided there is sufficientmoisture and shelter.Histrionicotoxin is a poison found on theskin of a certain tree frog in South America(Dendrobates histrionicus), and is used bythe native indians on their blow-pipe darts.
Histrionicotoxin, the structure of which is shown is a spirocyclic piperidine, andis one of a family of eleven compounds, which differ in their side-chains.Some exhibit acetylenic functionality (as in histrionicotoxin-HTX- itself), andothers have allenic side-chains or saturated side-chains.The spirocyclic core of the HTX family is unique in the world of natural productsand has therefore been the subject of much study in the chemical community.The cis-enyne moiety is also a very unusual feature in the natural productkingdom.The closest that nature comes to producing this type of unsaturation is in thebacterium-derived compounds known as enediynes, including such antibiotics ascalicheamicin, and also the neocarzinostatins, esperamicins and thedynemicins.The toxins that have been isolated originate from small glands on thebacks of the frogs, which were originally thought to produce, and then store thepoison.Interestingly, when the frogs are kept in captivity, the levels of the toxins that theyproduce is severely diminished, and in most species is not produced at all. Thishas led to the assertion nowadays that the toxins are somehow introduced into thefrog via diet or by some other outside influence.
Biological AspectsHTX has very similar spacial arrangements to the neurotransmitteracetylcholine. The distance between the nitrogen and the hydroxyl groups inboth acetylcholine and HTX is approximately 2.7 angstroms. It is due to thissimilarity that the toxin can affect the nervous system.The histrionicotoxins have been shown to be potent nicotinic non-competitive antagonists. This means that HTX acts as a ligand thatantagonises the response to acetylcholine without actually blocking thebinding sites of acetylcholine. The toxin has the ability to block the channelassociated with the protein-bound acetylcholine receptor known as the IMRC(ionic conductance modulator receptor complex). This causes a reduction inthe conductance across the channel and also a reduction in the time which thechannel is open.Unlike the highly toxic batrachotoxins (also derived from frogs) HTX shows afairly low toxicity level in mammals. An administered dose of 5-10 mg/Kg inmice only induces slight locomotive difficulties and prostration. Although themolecule has a low toxicity level, it does draw particular biological interestdue to its excellent selectivity for the nicotinic acetylcholine receptor
Chemical SynthesisSince the isolation and characterisation of the histrionicotoxins by J. W.Daly, the synthesis of these natural products has drawn considerableinterest.To date there have been three total syntheses, and various syntheses of theanalogues with saturated side-chains (eg. perhydrohistrionicotoxin).
Chemical SynthesisSince the isolation and characterisation of the histrionicotoxins by J. W. Daly, the synthesis of these natural products has drawn considerable interest.To date there have been three total syntheses, and various syntheses of the analogues with saturated side-chains (eg. perhydrohistrionicotoxin).rac-Histrionicotoxin (Kishi, 1985)Kishis route started with an advanced intermediate which he utilised for his previous synthesis of octahydro-HTX. Unfortunately, it was found that simultaneous introduction of the two side-chains was not possible, and therefore a stepwise approach was undertakenfor installing these chains individually.
(-)-Histrionicotoxin (Stork, 1990)Five years after Kishis total synthesis, the Stork grouppublished their work on the first asymmetric synthesis of (-)-HTX. In this elegant synthesis, new methodology was developed specifically with a viewto installing the cis-enyne side-chains. Stork also used work previously used in his group for the creation of the quaternary centre in a stereoselective fashion.
(-)-Histrionicotoxin (Holmes, 1999)The Holmes synthesis used novel methodology to create the spiropiperidine core, and then utilised chemistry similar to that of Stork for the introduction of the cis-enyne side-chainsThe key features of the synthesis are an amine-alkyne cyclisation to produce an optically pure nitrone, which then underwent an intramolecular [3+2] nitrone cycloaddition to give the basic skeleton of HTX.
The synthesis was published in J. Am. Chem. Soc. in 2006.
new approach to spirocyclic and angularly fused tricyclic synthetic intermediatesthrough the employment of tandem ring closing metathesis (RCM) reactions. It isindicated that a range of polyolefinic precursors undergo selective RCM reactionsto provide the desired synthetic intermediates in a selective manner.
The target, histrionicotoxin 285A, was (likethe rest of the family) isolated by blendingpoison-arrow frogs, and turns out to be apretty potent inhibitor of the nicotinicacetylcholine receptor.Â Although there’sbeen loads of work on HTX 283A (includinga synthesis by the group back in 2004, andeven further back in 1999…), this is the firstsynthesis of 285A, using a strategy familiarto the group.Â This utilises a key nitronedipolar cycloaddition:
Org. Lett., 2011, 13 (16), pp 4446–4449A total synthesis of (−)-histrionicotoxin was achieved. Our synthesisfeatures preparation of a pseudosymmetrical dienyne through chiralitytransfer from an allenylsilane, a dienyne metathesis to produce thebicyclo [5.4.0] system in optically active form, selective functionalizationof a diene via a 5-exo-trig iodoetherification, and an asymmetricpropargylation.
Links to other interesting sitesFor a selection of poison dart frog related links, try one of these, oralternatively try using a search engine such as Yahoo or AltaVistawith keywords such as poison dart frogs or dendrobates forexample.Poison Dart FrogsPoison Dart Frog (Dendrobates pumilio)The Dendrobates tinctorius Color Morph GuideThe Dartfrog Gallery
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