Allopumiliotoxins are a structural division in the pumiliotoxin-A class of

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

s. The compounds of the pumiliotoxin-A class are primarily found in the skins of frogs, toads, and other amphibians and are used as a chemical defense mechanism to ward off

predator Predation is a biological interaction where one organism, the predator, kills and eats another organism, its prey. It is one of a family of common feeding behaviours that includes parasitism and micropredation (which usually do not kill th ...

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s, and

ectoparasite Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...

s. The compounds were originally discovered in neotropical dendrobatid frogs, but are also found in the mantellid frogs of

Madagascar Madagascar (; mg, Madagasikara, ), officially the Republic of Madagascar ( mg, Repoblikan'i Madagasikara, links=no, ; french: République de Madagascar), is an island country in the Indian Ocean, approximately off the coast of East Africa ...

, myobatrachid frogs of

Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...

, and bufonid toad of

South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere at the northern tip of the continent. It can also be described as the southe ...

. Frogs possessing this defense mechanism have

aposematic Aposematism is the advertising by an animal to potential predators that it is not worth attacking or eating. This unprofitability may consist of any defences which make the prey difficult to kill and eat, such as toxicity, venom, foul taste or ...

coloring.Jain, P.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J. W. J. Nat. Prod. 1995, 58, 100-104.

Biological activity

The poison-dart frog family

Dendrobatidae Poison dart frog (also known as dart-poison frog, poison frog or formerly known as poison arrow frog) is the common name of a group of frogs in the Family (biology), family Dendrobatidae which are native to tropical Central and South America. T ...

has yielded many different alkaloids categorized into several different classes, almost all of which have shown high pharmacological activity on muscle and nerve cells.Aoyagi, S.; Wang, T. C.; Kibayashi, C. J. Am. Chem. Soc. 1993, 115, 11393-11409. The pumiliotoxin-A class, specifically, contains many molecules which have had a favorable effect on the heart. Allopumiliotoxins, the most complex member of this class, have a wide range of biological activities, the full understanding of which has not been fully discerned due their incredible complexity and subsequent synthetic difficulties. Among allopumiliotoxins, those with a β-oriented C-7

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...

have shown greater activity in comparison to α-epimers of this position. Allopumiliotoxin 339A has been shown to stimulate sodium influx and phosphoinositide breakdown in the cerebral cortical synaptoneurosomes of

guinea pigs The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus ''Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ani ...

and is one of the most active allopumiliotoxins. It is more biologically active than pumiliotoxin B, which has had similar biological effects on the secondary messenger system, causing muscle rigidity and some favorable effects on the heart. Pumiliotoxins and allopumiliotoxins are very toxic in general. Pumiliotoxin B has caused death in

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

when 20 μg was given in injections below the skinFranklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 502-522.

Nomenclature

There are three divisions within the pumiliotoxin-A class: allopumiliotoxins, pumiliotoxins, and homopumiliotoxins. Once the compound’s specific class is determined, it’s given a number based on its molecular weight. These biologically active compounds are complex and have structural variations that allow for specific molecular recognition. Therefore, the way 2

isomers In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

are differentiated is by a letter after the number. Therefore, for example, allopumiliotoxin 339A is an allopumiliotoxin with a

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of 339 g/mol but there are other isomers with the same molecular weight. Allopumiliotoxin 339A has an axially oriented hydroxyl group at the 7-position in the

indolizidine Indolizidine is a heterocyclic chemical compound that forms the central core of the indolizidine alkaloids such as swainsonine and castanospermine. See also * Indole * Indolizine * Tryptophan * Tryptamine Tryptamine is an indolamine metabol ...

nucleus that differentiates it from allopumiliotoxin 339B. A (+) or (-) sign preceding the name of an allopumiliotoxin refers to the compound’s optical activity. Compounds that rotate a plane of polarized light clockwise are referred to as dextrorotatory and are preceded by a (+) sign. Compounds that rotate a plane of polarized light counterclockwise are referred to as levorotatory and are preceded by a (-) sign.

Structure

The different divisions of compounds in the pumiliotoxin-A class arise from differences in the carbon backbone and/or the substituents attached to it. The difference between allopumiliotoxins and pumiliotoxins occurs at the 7 position. At this position, allopumiliotoxins have a

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

substituent whereas pumiliotoxins have a

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

. Both have

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

and hydroxyl groups at the C-8 position. Homopumiliotoxins contain a

quinolizidine Quinolizidine (norlupinane, octahydro-2''H''-quinolizine) is a nitrogen-containing heterocyclic compound. Some alkaloids (e.g. cytisine and sparteine) are derivatives of quinolizidine. Quinolizidine alkaloids Quinolizidine alkaloids, such as ...

ring in the place of the indolizidine ring and methyl and hydroxyl groups at its C-9 position. All three contain an alkylidenyl side-chain.

Isolation

As stated previously, these alkaloids were first discovered in the skins of frogs. They can be isolated from the frog’s skin by mincing the skin and extracting the compounds by

trituration Trituration (Latin, ''grinding'') is the name of several different methods used to process materials. In one sense, it is a form of comminution (reducing the particle size of a substance). In another sense, it is the production of a homogeneous pow ...

. A series of extractions involving an acid-base extraction are needed to isolate the allopumiliotoxins. The skins of the frogs may contain a number of different allopumiliotoxins. For example, the skin of

Dendrobates ''Dendrobates'' is a genus of poison dart frogs native to Central and South America. It once contained numerous species, but most originally placed in this genus have been split off into other genera such as ''Adelphobates'', '' Ameerega'', '' A ...

tricolor was found to contain alkaloids 251D, 271, 341A, and 323B. Also, different frogs contain different alkaloids in their skin.

Dendrobates auratus The green-and-black poison dart frog (''Dendrobates auratus''), also known as the green-and-black poison arrow frog and green poison frog (among others), is a brightly colored member of the order Anura native to Central America and northwestern ...

, for example, was found to contain (+)-allopumiliotoxin 339A (a compound not present in the skin of Dendrobates tricolor).Aoyagi, S.; Wang, T. C.; Kibayashi, C. J. Am. Chem. Soc. 1992, 114, 10653-10654.

Synthesis

Allopumiliotoxins are very biologically useful but are rare in nature. For this reason, many groups have researched syntheses for various

alkaloids Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar st ...

of this type. The main problem with allopumiliotoxin synthesis arises from the alkylidene side chain because the

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

of it can be difficult to control by

Wittig Wittig is a surname, and may refer to: * Burghardt Wittig (born 1947), German biochemist * Curt Wittig, American chemist * David Wittig (born 1955), American executive * Edward Wittig (1879–1941), Polish sculptor * Ferdinand Wittig (1851-1909 ...

-type functionalizations. Total synthesis of (+)-allopumiliotoxin 267A was achieved using a

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

dihydropyridone intermediate that was formed from the addition of ethyl lithiopropiolate to the N-acylpyridinium salt which results from the reaction of (+)-trans-2-(α-cumyl)cyclohexyl chloroformate and 4-methoxy-3-methyl-5(triisopropylsilyl)pyridine. This intermediate was then subjected to various additions and oxidations to yield the final allopumiliotoxin. The synthesis of (+)-allopumiliotoxin 323B’ has also been achieved using an intermediate from the previous synthesis.Michael, J. P. Nat. Prod. Rep. 2002, 19, 719-741. (+)-Allopumiliotoxin 339A has been synthesized using an iodide-promoted

iminium ion In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...

alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...

cyclization followed by condensation with acetylenic salt. Subsequent reactions led to the

enantiopure In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

product after 16 steps and a 7.5% yield. Other synthetic methods have been carried out for this molecule. One of which was achieved through the use of a Nozaki-Kishi Cyclization. Allopumiliotoxin 267A was synthesized using a similar cyclization.

Analysis

The pumiliotoxin-A class compounds are typically analyzed by GC-MS because the different classes show different prominent peaks. Allopumiliotoxins show corresponding ions of C₄H₈N⁺(m/z 70) and C₁₀H₁₆NO₂⁺(m/z 182). The mass spectra of pumiliotoxins show prominent ions of C₄H₈N⁺ (m/z 70) and C₁₀H₁₆NO⁺ (m/z 166). Homopumiliotoxins exhibit prominent mass spectral fragment ions of C₅H₁₀N⁺ (m/z 84) and C₁₁H₁₈NO⁺ (m/z 180).

References

{{Reflist, 30em Vertebrate toxins Alkaloids Secondary alcohols Tertiary alcohols Indolizidines