Histrionicotoxin is a poison found in the skin of Dendrobates histrionicus, a type of poison dart frog found in South America. In the 1800s, tribes in Colombia and other parts of South America extracted the poison from these frogs and coated their hunting arrows and blow darts with it. The poison acts as a nicotinic acetylcholine receptor antagonist, paralyzing prey. Since the frogs were first reported on by a British explorer in 1823, scientists have studied histrionicotoxin's chemical structure and properties, as well as developing synthetic versions of the toxin.

1. A SHORT PRESENTATION
Jan 2012
Histrionicotoxin
from South American poison-dart frogs

2. In 1823, a western traveller by the name of Captain Charles Stuart Cochrane reported
on his expeditions around the lowland tropical rain forests of Colombia. He
encountered tribes of native Indians who used poison arrows and blowgun darts for
hunting.
Eventually, He discovered that the poison had been been extracted from small
brightly coloured frogs.
One of these poisons is called histrionicotoxin, named after the subspecies from
which it is extracted, Dendrobates histrionicus.

3. 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 it
perspires more than normal and causes it to release a white foam on it's back.
The frogs can be found in the lowland tropical rain forests or in the
mountains, 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 blowgun
darts with the compound when they went hunting.

4. The frogs which Cochrane wrote about
belong to any one of the
families Dendrobates,Phyllobates, Atropophr
ynus and Colostethus, and are characterised
by their highly coloured markings, which
advertise the poisonous nature of these
creatures in an attempt to warn off
predators. Their habitat ranges from the
lowland tropical rainforests to arid
mountain areas and are generally confined
to South and Central America. Some species
are found next to rivers and streams or in
damp shaded areas, whereas others spend
their time in trees or even in dry open
country, provided there is sufficient
moisture and shelter.
Histrionicotoxin is a poison found on the
skin of a certain tree frog in South America
(Dendrobates histrionicus), and is used by
the native indians on their blow-pipe darts.

5. Histrionicotoxin, the structure of which is shown is a spirocyclic piperidine, and
is one of a family of eleven compounds, which differ in their side-chains.
Some exhibit acetylenic functionality (as in histrionicotoxin-HTX- itself), and
others have allenic side-chains or saturated side-chains.
The spirocyclic core of the HTX family is unique in the world of natural products
and 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 product
kingdom.
The closest that nature comes to producing this type of unsaturation is in the
bacterium-derived compounds known as enediynes, including such antibiotics as
calicheamicin, and also the neocarzinostatins, esperamicins and the
dynemicins.The toxins that have been isolated originate from small glands on the
backs of the frogs, which were originally thought to produce, and then store the
poison.
Interestingly, when the frogs are kept in captivity, the levels of the toxins that they
produce is severely diminished, and in most species is not produced at all. This
has led to the assertion nowadays that the toxins are somehow introduced into the
frog via diet or by some other outside influence.

6. Biological Aspects
HTX has very similar spacial arrangements to the neurotransmitter
acetylcholine. The distance between the nitrogen and the hydroxyl groups in
both acetylcholine and HTX is approximately 2.7 angstroms. It is due to this
similarity 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 that
antagonises the response to acetylcholine without actually blocking the
binding sites of acetylcholine. The toxin has the ability to block the channel
associated with the protein-bound acetylcholine receptor known as the IMRC
(ionic conductance modulator receptor complex). This causes a reduction in
the conductance across the channel and also a reduction in the time which the
channel is open.
Unlike the highly toxic batrachotoxins (also derived from frogs) HTX shows a
fairly low toxicity level in mammals. An administered dose of 5-10 mg/Kg in
mice only induces slight locomotive difficulties and prostration. Although the
molecule has a low toxicity level, it does draw particular biological interest
due to its excellent selectivity for the nicotinic acetylcholine receptor

7. Chemical Synthesis
Since 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).

9. Chemical Synthesis
Since 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)
Kishi's 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 undertaken
for installing these chains individually.

10. (-)-Histrionicotoxin (Stork, 1990)
Five years after Kishi's total synthesis, the Stork group
published their work on the first asymmetric synthesis of (-)-HTX.
In this elegant synthesis, new methodology was developed specifically with a view
to 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.

11. (-)-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-chains
The 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.

13. --

14. The synthesis was published in J. Am. Chem. Soc. in 2006.

15. new approach to spirocyclic and angularly fused tricyclic synthetic intermediates
through the employment of tandem ring closing metathesis (RCM) reactions. It is
indicated that a range of polyolefinic precursors undergo selective RCM reactions
to provide the desired synthetic intermediates in a selective manner.

16. The target, histrionicotoxin 285A, was (like
the rest of the family) isolated by blending
poison-arrow frogs, and turns out to be a
pretty potent inhibitor of the nicotinic
acetylcholine receptor. Although there’s
been loads of work on HTX 283A (including
a synthesis by the group back in 2004, and
even further back in 1999…), this is the first
synthesis of 285A, using a strategy familiar
to the group. This utilises a key nitrone
dipolar cycloaddition:

21. Org. Lett., 2011, 13 (16), pp 4446–4449
A total synthesis of (−)-histrionicotoxin was achieved. Our synthesis
features preparation of a pseudosymmetrical dienyne through chirality
transfer from an allenylsilane, a dienyne metathesis to produce the
bicyclo [5.4.0] system in optically active form, selective functionalization
of a diene via a 5-exo-trig iodoetherification, and an asymmetric
propargylation.

25. Links to other interesting sites
For a selection of poison dart frog related links, try one of these, or
alternatively try using a search engine such as Yahoo or AltaVista
with keywords such as 'poison dart frogs' or 'dendrobates' for
example.
Poison Dart Frogs
Poison Dart Frog (Dendrobates pumilio)
The Dendrobates tinctorius Color Morph Guide
The Dartfrog Gallery

26. THANKS AND REGARD'S
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
web links
https://sites.google.com/site/amcrasto/http://www.slidestaxx.com/anthon
y-melvin-crasto-phd
https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-
own-on-the-net
http://anthonycrasto.wordpress.com/
http://organicchemistrysite.blogspot.com/
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