Pumiliotoxin 251D

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Pumiliotoxin 251D
Pumiliotoxin251D.png
Names
Preferred IUPAC name
(6Z,8S,8aS)-8-Methyl-6-[(2R)-2-methylhexylidene]octahydroindolizin-8-ol
Other names
Pumiliotoxin 251D
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
  • InChI=1S/C16H29NO/c1-4-5-7-13(2)10-14-11-16(3,18)15-8-6-9-17(15)12-14/h10,13,15,18H,4-9,11-12H2,1-3H3/b14-10-/t13-,15+,16+/m1/s1 X mark.svgN
    Key: OKTQTXDNHCOLHT-AJKPHIATSA-N X mark.svgN
  • InChI=1/C16H29NO/c1-4-5-7-13(2)10-14-11-16(3,18)15-8-6-9-17(15)12-14/h10,13,15,18H,4-9,11-12H2,1-3H3/b14-10-/t13-,15+,16+/m1/s1
    Key: OKTQTXDNHCOLHT-AJKPHIATBP
  • O[C@]1(CC(=C\[C@H](C)CCCC)\CN2[C@H]1CCC2)C
Properties
C16H29NO
Molar mass 251.414 g·mol−1
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Toxic
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Pumiliotoxin 251D is a toxic organic compound. It is found in the skin of poison frogs from the genera Dendrobates , Epipedobates , Minyobates , and Phyllobates [1] [2] and toads from the genus Melanophryniscus . [3] Its name comes from the pumiliotoxin family (PTXs) and its molecular mass of 251 daltons. When the toxin enters the bloodstream through cuts in the skin or by ingestion, [4] it can cause hyperactivity, convulsions, cardiac arrest and ultimately death. It is especially toxic to arthropods (e.g. mosquitoes), even at low (naturally occurring) concentrations. [5]

Contents

Chemical properties

Structure

The chiral centers in pumiliotoxin 251D can give several stereoisomers of the compound. Only one form of the toxin is present in nature and has toxic properties.

PTX (+) and (-).jpg

Two enantiomers of pumiliotoxin 251D. On the left the plus enantiomer is shown which is toxic. On the right side the minus enantiomer, which is not toxic, is shown.

The side chain conformation of substituents at the C-2’ position plays an important role in the toxicity of the compound. [6]

Synthesis

The synthesis of pumiliotoxin 251D is quite complex and contains multiple steps.

One of the starting materials of the synthesis include the N-Boc derivative of L-proline methyl ester (1). Then, a Wittig type of reaction followed by dehydration with thionyl chloride and pyridine results in alkene 2. When alkene 2 undergoes epoxidation with m-chloroperbenzoic acid (MCPBA), epoxide 3 is formed. This then reacts with the lithium salt of dibromoalkene (6) to afford compound 7. Deprotection of compound 7 followed by cyclization and iodination results in vinyl iodide 8. After purification, this yields the hydrochloride of pumiliotoxin (+)-251D (9).

Pumiliotoxin (−)-251D can be synthesized in a similar way with minor alterations to the overall synthesis. [6]

Accumulation

Like many other frog poisons, pumiliotoxin 251D originates from arthropods. [6] [7] [8] The frogs have a diet of insects that could contain the toxin then it is accumulated in secretory granular glands of the skin of the frog. [6] Some frog species of the Dendrobates genera can convert pumiliotoxin 251D in allopumiliotoxin 267A which is five times more toxic than pumiliotoxin 251D. [6] [9] Only one of the enantiomers can be hydroxylated to this more potent form of the toxin.

The lack of pumiliotoxin 251D in eggs and tadpoles confirms that the toxin is not passed over from adult frogs to their offspring. [4] The tadpoles are therefore not readily protected from predators.

Toxicity

Mechanism of action

In general, pumiliotoxins are known as positive modulators of voltage-gated sodium channels (VGSCs, membrane proteins). Pumiliotoxin 251D is not such a poison. However, it does block the influx of Na+ ions in mammalian VGSCs.

Pumiliotoxin 251D is able to shift the V1/2. This is the potential at which the sodium open probability is half maximal. Both the steady-state activation and inactivation curves of each mammalian VGSCs are shifted to a more negative potential. [1]

PTX 251D shifts the V1/2 of insect VGSCs even further than the mammalian VSGCs. This explains why it is especially toxic to insects, like mosquitoes. Furthermore, the presence of PTX 251D results in a six time higher permeability of the VGSCs for K+ ions. This severely disturbs the delicate sodium-potassium equilibrium in the nerve system.

The effect of pumiliotoxin 251D on the voltage-gated potassium channels (VGPCs) currents is quite small. The toxic has an effect on the deactivation kinetics of the potassium channel. It inhibits its inactivation. This effect is still under investigation. [1]

PTX 251D also completely inhibits the activity of Ca2+-stimulated ATPase. [10] This results in a decreased reuptake of Ca2+ and thus a high concentration of free Ca2+ in the organism. This may be related to the potentiation and prolongation of muscle twitch caused by the inhibition. [10]

The mechanism of biotransformation of PTX 251D is still unknown.

Effects

Pumiliotoxin is a toxin found in poison dart frogs (genus Dendrobates and Phyllobates). It affects the calcium channels, interfering with muscle contraction in the heart and skeletal muscle.

PTX 251D has several effects. It rapidly induces convulsions and death to mice and insects (LD50 being, respectively, 10 mg/kg and 150 ng/larvae). [1] These convulsions are the result of the uncontrollable distortion of the sodium-potassium equilibrium in the neurons. This is caused by the inhibition of the VGSCs.

It also acts as cardiac depressor, causing cardiac arrest. This can be explained by its negative effect on the cardiac VGSC hNav1.5/β1. [1]

Although nothing is known of how well PTX 251D penetrates into the brain where convulsions are originated, the observation of convulsions can be explained through inhibition of VGPCs. [1]

Treatment

Symptomatic treatment of PTX 251D poisoning include reducing the convulsions using carbamazepine. This drug targets the affected VGSCs. Phenobarbital also shows positive effects by interacting with the affected Ca2+ channels. Ineffective drugs include diazepam and dizocilpine. [1]

Related Research Articles

<span class="mw-page-title-main">Poison dart frog</span> Family of amphibians

Poison dart frog is the common name of a group of frogs in the family Dendrobatidae which are native to tropical Central and South America. These species are diurnal and often have brightly colored bodies. This bright coloration is correlated with the toxicity of the species, making them aposematic. Some species of the family Dendrobatidae exhibit extremely bright coloration along with high toxicity, while others have cryptic coloration with minimal to no amount of observed toxicity. The species that have great toxicity derive this feature from their diet of ants, mites and termites. However, other species that exhibit cryptic coloration, and low to no amounts of toxicity, eat a much larger variety of prey. Many species of this family are threatened due to human infrastructure encroaching on their habitats.

<span class="mw-page-title-main">Batrachotoxin</span> Chemical compound

Batrachotoxin (BTX) is an extremely potent cardio- and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. In certain frogs, this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.

<span class="mw-page-title-main">Cerberin</span> Chemical compound

Cerberin is a type of cardiac glycoside, a steroidal class found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. This class includes digitalis-like agents, channel-blockers that as a group have found historic uses as cardiac treatments, but which at higher doses are extremely toxic; in the case of cerberin, consumption of the C. odollam results in poisoning with presenting nausea, vomiting, and abdominal pain, often leading to death. The natural product has been structurally characterized, its toxicity is clear—it is often used as an intentional human poison in third-world countries, and accidental poisonings with fatalities have resulted from individuals even indirectly consuming the agent—but its potentially therapeutic pharmacologic properties are very poorly described.

<span class="mw-page-title-main">Strawberry poison-dart frog</span> Species of amphibian

The strawberry poison frog, strawberry poison-dart frog or blue jeans poison frog is a species of small poison dart frog found in Central America. It is common throughout its range, which extends from eastern central Nicaragua through Costa Rica and northwestern Panamá. The species is often found in humid lowlands and premontane forest, but large populations are also found in disturbed areas such as plantations. The strawberry poison frog is perhaps most famous for its widespread variation in coloration, comprising approximately 15–30 color morphs, most of which are presumed to be true-breeding. O. pumilio, while not the most poisonous of the dendrobatids, is the most toxic member of its genus.

<span class="mw-page-title-main">Dyeing poison dart frog</span> Species of amphibian

The dyeing dart frog, cobalt poison frog, dyeing poison dart frog, tinc, or dyeing poison frog is a species of poison dart frog. It is among the largest species, reaching lengths of 50 mm (2.0 in). This species is distributed throughout the eastern portion of the Guiana Shield and Venezuela, including parts of Guyana, Suriname, Brazil, and nearly all of French Guiana.

<span class="mw-page-title-main">Golden poison frog</span> Species of amphibian

The golden poison frog, also known as the golden dart frog or golden poison arrow frog, is a poison dart frog endemic to the rainforests of Colombia. The golden poison frog has become endangered due to habitat destruction within its naturally limited range. Despite its small size, this frog is among the most poisonous animals on the planet.

<i>Phyllobates</i> Genus of amphibians

Phyllobates is a genus of poison dart frogs native to Central and South America, from Nicaragua to Colombia. There are 3 different Colombian species of Phyllobates, considered highly toxic species due to the poison they contain in the wild.

<i>Phyllobates aurotaenia</i> Species of amphibian

Phyllobates aurotaenia is a member of the frog family Dendrobatidae, which are found in the tropical environments of Central and South America. First described by zoologist George Albert Boulenger in 1913, P. aurotaenia is known for being the third most poisonous frog in the world. It is the smallest of the poison dart frogs in the Phyllobates genus and is endemic to the Pacific coast of Colombia.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

<i>Oophaga sylvatica</i> Species of amphibian

Oophaga sylvatica, sometimes known as its Spanish name diablito, is a species of frog in the family Dendrobatidae found in Southwestern Colombia and Northwestern Ecuador. Its natural habitat is lowland and submontane rainforest; it can, however, survive in moderately degraded areas, at least in the more humid parts of its range. It is a very common frog in Colombia, but has disappeared from much of its Ecuadorian range. It is threatened by habitat loss (deforestation) and agricultural pollution and sometimes seen in the international pet trade.

<span class="mw-page-title-main">Golfodulcean poison frog</span> Species of amphibian

The Golfodulcean poison frog or Golfodulcean poison-arrow frog is a species of frog in the family Dendrobatidae endemic to Costa Rica.

<span class="mw-page-title-main">Pumiliotoxin</span>

Pumiliotoxins (PTXs), are one of several toxins found in the skin of poison dart frogs. The frog species, P. bibronii also produces PTXs to deter predators. Closely related, though more toxic, are allopumiliotoxins, (aPTXs). Other toxins found in the skin of poison frogs include decahydroquinolines (DHQs), izidines, coccinellines, and spiropyrrolizidine alkaloids. Pumiliotoxins are very poisonous in high concentrations. Pumiliotoxins are much weaker than batrachotoxins, ranging between 100 and 1000 times less poisonous. There are three different types of this toxin: A, B and C, of which toxins A and B are more toxic than C. Pumiliotoxins interfere with muscle contraction by affecting calcium channels, causing partial paralysis, difficulty moving, hyperactivity, or death. The median lethal dose of pumiliotoxins A and B is 50 µg / mouse, 20 µg / mouse respectively, while the amount of pumiliotoxin is 200 µg / frog.

<span class="mw-page-title-main">Allopumiliotoxin 267A</span> Chemical compound

Allopumiliotoxin 267A is a toxin found in the skin of several poison frogs of the family Dendrobates. It is a member of the class of compounds known as allopumiliotoxins. The frogs produce the toxin by modifying the original version, pumiliotoxin 251D. It has been tested on mice and found to be five times more potent than the former version. It has been produced synthetically through a variety of different routes.

<span class="mw-page-title-main">Allopumiliotoxin</span> Group of chemical compounds

Allopumiliotoxins are a structural division in the pumiliotoxin-A class of alkaloids. 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 predators, microorganisms, and ectoparasites. The compounds were originally discovered in neotropical dendrobatid frogs, but are also found in the mantellid frogs of Madagascar, myobatrachid frogs of Australia, and bufonid toad of South America. Frogs possessing this defense mechanism have aposematic coloring.

<span class="mw-page-title-main">Histrionicotoxins</span>

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<i>Adelphobates</i> Genus of amphibians

Adelphobates is a small genus of poison dart frogs. They are found in the central and lower Amazon basin of Peru and Brazil, possibly Bolivia. It was originally erected as a sister group to the Dendrobates and Oophaga genera. The validity of the genus is still being discussed, with the alternative being "Dendrobates galactonotus group" within Dendrobates. One species originally placed in this genus as Adelphobates captivus has since been moved to the genus Excidobates erected in 2008.

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<span class="mw-page-title-main">Neosaxitoxin</span> Chemical compound

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<span class="mw-page-title-main">Dioscorine</span> Chemical compound

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Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.

References

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