Of amphibian alkaloids

The batrachotoxins were the first class of unique alkaloids to be characterized from skin extracts of frogs of the family Dendrobatidae (see ref. 23 for a review of amphibian alkaloids). Batrachotoxin was detected in only five species of dendrobatid frogs and these frogs were then classified as the monophyletic genus Phyllobates, based in part on the presence of batrachotoxins (24). However, levels of batrachotoxins differ considerably, with the Colombian Phyllobates terribilis containing nearly 1 mg of batrachotoxins per frog, while the somewhat smaller Phyllobates bicolor and Phyllobates aurotaenia, also from the rain forests of the Pacific versant in Colombia, contain 10-fold lower skin levels (8). The two... 

A number of reviews in the last decade (i-5) have focused on synthesis of amphibian alkaloids. The present chapter will not treat synthesis but will document only the structural diversity, spectral and chemical properties, biological activity, and distribution in Nature of the nearly 300 known amphibian alkaloids. 

Disubstituted indolizidines, unlike many classes of amphibian alkaloids, are not unique to amphibians. 3,5-Disubstituted indolizidines such as monomorine I [(5Z,9Z)-195B] occur in ants of the genera Monomorium and Solenopsis (125,129,134). Some of the ant indolizidines are as follows (5Z,9Z)-3-n-butyl-5-methylindolizidine (monomorine I), (5Z,9Z)-3- -ethyl-5-methylindolizidine, (5Z,9Z)-3-hexyl-5-methylindolizidine, and (5 ,9Z)-3-butyl-5-(4-pentenyl)indolizidine. A series of 5-substituted indolizidines, the piclavines, were reported recently from a marine tunicate (Clavelina picta) (135). 

A major class of amphibian alkaloids was recently discovered in frogs of the myobatrachid genus Pseudophryne (86,119). These represent the unidentified indolic compounds first noted by Erspamer and co-workers in 1976 (169). Isolation of two of these indole alkaloids from partially purified extracts of Pseudophryne coriacea allowed structure elucidation of pseudophrynaminol (XIV) and pseudophrynamine A (XV) by nuclear magnetic resonance spectral analysis (119). Methoxide cleavage of pseudophrynamine A yielded pseudophrynaminol and a methyl ester... 

In 1999 the late Dr John Daly, the doyen of researchers in the field of amphibian alkaloids, and two of his regular colleagues published a major survey of alkaloids isolated from, or detected in, extracts from the granular glands in amphibian skin. Their review listed over 500 alkaloids, both well characterized and tentative. This survey was followed by a short personal perspective in which Daly described the discovery and identification of biologically active alkaloids in amphibian skin, and the subsequent confirmation of arthropods as the dietary source of many of these compounds. The survey of 1999 was subsequently superseded by an even more... 

In their comprehensive 2005 survey of amphibian alkaloids, Daly and colleagues reported that about 80 5,8-disubstituted indolizidines had been fuUy or tentatively characterized at that stage, making it the largest class of alka-... 

The pumiliotoxins, alio- and homopumiliotoxins, are alkaloids isolated from the skin of amphibians, such as neotropical frogs of the Dendrobatidae family, and are believed to serve as a chemical defence against predators. These natural products have interesting pharmacological properties, including myotonic and cardiotonic activities. 

The most well known and most widely used compounds mentioned in the chapter are the doubly protected monosaccharide derivatives (cf. Schemes 16-18 and 27-29), which serve as building blocks for the regio- and stereospecific synthesis of a host of more complex carbohydrates. A number of newly discovered alkaloids contain fused 5 6 6-triheterocyclic systems these compounds may come from not only traditional (plant) sources, for example, compounds 96, 292-294, 446, and 447, but also insects (compounds 531-533), marine animals of various kinds, for example, sponges (compounds 58 R = H or OH) and ascidians (compound 289), and amphibians (compound 535). Although the majority of these alkaloids are known to be toxic in sufficient quantity, any possible therapeutic applications have apparently not yet been disclosed. 

In the overall cycloaddition-rearrangement process [64], the C-3 - C-8a relative stereochemistry of the indolizidinone obtained by rearrangement of the isoxazolidine derives from the cycloaddition step and is not affected during the rearrangement. This allowed the control of two out of three chiral centers in a synthetic protocol for a synthesis of the amphibian alkaloid ( + )-Gephyro-toxin 223AB (Scheme 46) [65c]. 

The isoxazoline 355 (Table 27, entry 9) served as precursor for the total synthesis of the amphibian alkaloid ( + )-Pumiliotoxin C 358 (Scheme 50) [89]. 

Three of the classes of compounds found from the skin of amphibians have been identified from the skin of bufonids, including Bufo marinus. These are steroids (bufadienolides), biogenic amines (catecholamines, indolylalkylamines and alkaloids) and bioactive peptides and proteins. 

FIGURE 1 Structures of lipophilic amphibian alkaloids. Alkaloids indicated by asterisks represent structural classes that have not been detected in nature except in amphibians and, in the case of batrachotoxins, in one species of bird (9). 

Another class of these amphibian alkaloids, the pumiliotoxins, contain an alkylidene side chain on C-6 of the indolizidine ring (Table 2). Due to their myotonic and cardiotonic activity, and challenging structure, they also have been the object of synthetic interest. A review points out the state of the art at the beginning of the decade <1996CRV505>. 

The neotropical dart poison frogs contain a remarkable diversity of alkaloids, and the 2,5-disubstituted decahydroquinolines represent, a major class of these amphibian alkaloids[21]. Isolation of these alkaloids from some ants strengthens a dietary hypothesis for the origin of the above alkaloids that have been detected in extracts of frog skin[22]. In addition, these alkaloids containing both cis and trans ring fusion have been identified as well as diastereomers at the C-2 and C-5 position. 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

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