Dendrobatid frog 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... 

Two classes of dendrobatid alkaloids have potential dietary sources. The first are the pyrrolizidine oximes (32), whose carbon skeleton is identical to that of nitropolyzonamine, an alkaloid from a small millipede (33). Indeed, raising the dendrobatid frog D. auratus in Panama on leaf-litter arthropods, gathered weekly, resulted in skin levels of the... 

The proposal that all alkaloids found in skin glands of dendrobatid frogs and used in chemical defense against predators have a dietary origin leads to many questions. First, the profile of alkaloids has been found in many instances to be characteristic of a species or a population. 

Daly, J. W, Garaffo, H. M., Jain, P., etal. (2000). Arthropod-frog connection decahydro-quinoline and pyrrolizidine alkaloids common to microsympatric myrmicine ants and dendrobatid frogs. Journal of Chemical Ecology 16,73-85. 

ASIDE Alkaloid toxins found in dendrobatid frogs... 

Dendrobatid toxins. The first step in a synthesis of ( )-perhydrogephyrotoxin (S, a poison-frog alkaloid) involves a Diels-Alder reaction of 1 and a suitable a.ft-unsulurated aldehyde, which proceeds selectively to give the erafo-adduct 2. Another key step is the selective reduction of a bicyclic imine (3) with LiAlH4 in about 9 1 ratio from the sterically more hindered a-face.2... 

The above three alkaloids are found in the skins of dendrobatid frogs of the genus Phyllobates terribilis, P. aurotaenia, and P. bicolor, all of Colombia, and to a very minor extent in P. vittatus of Costa Rica and P. lugubris of Panama (28). 

In contrast to dendrobatid alkaloids, which are not present in captive-raised dendrobatid frogs, lire salamanders produce samandarine alkaloids when reared in captivity (G. Habermehl, personal communication, 1989). No apparent differences in alkaloid content occurred for at least three generations. Incubation of secretions from salamander parotoid glands with radiolabeled cholesterol in buffer for 3 days at room temperature led to some apparent incorporation of radioactivity into samandarine alkaloids (53). 

Histrionicotoxins represent a unique structural class of alkaloids found only in dendrobatid frogs (see below). Somewhat similar hydroxy-azaspiro-undecanes, namely, sibirine, nitramine, and isonitramine, occur in certain plants of the genus Nitraria (cf. Ref. 70). 

The first decahydroquinoline found in amphibians was isolated, along with two other alkaloids, from skin extracts of a Panamanian dendrobatid frog, Dendrobates pumilio. The three alkaloids were designated pumiJio-toxins A, B, and C (74,75). Pumiliotoxins A and B were quite toxic, and... 

Simple 2,5-disubstituted decahydroquinolines do not appear to have been reported to occur in Nature except in certain amphibians. Decahydroquinolines, like histrionicotoxins, occur in a range of dendrobatid frogs. These two classes of dendrobatid alkaloids often occur together in the same species or population. Indeed, the 19-carbon decahydroquinoline 269AB (or 269A and 269B) always appears to accompany the 19-carbon... 

The apparent occurrence of decahydroquinolines as major alkaloids in dendrobatid frogs of the genera Dendrobates, Epipedobates, and Phyllobates, and in bufonid toads of the genus Melanophryniscus, strongly suggests the independent evolutionary development of biosynthetic pathways to decahydroquinolines in two separate amphibian lineages. 

Fig. 8. Pumiliotoxin-A class alkaloids isolated as apparent artifacts from dendrobatid frogs (75). Epimerization or reaction with methanol does not occur at the allylic hydroxyl of 323A, apparently because of the additional adjacent hydroxyl group. O-Methyl-307A formerly was designated 321 (1,79). N-Oxides of pumiliotoxin 323A and allopumiliotoxin 267A have been isolated and may be artifactual (87).

Fig. 9. Structures of homopumiliotoxins from dendrobatid frogs and bufonid toads. The structure of homopumiliotoxin 223G is based on nuclear magnetic resonance spectral analysis (77). The absolute configuration is unknown. Homopumiliotoxin 223G occurs in dendrobatids (77), ranids (73), and bufonids (8 ), while the other alkaloids have been detected only in the bufonid toads (Melanophryniscus) (81).

Over 30 amphibian alkaloids from dendrobatid frogs, bufonid toads, or ranid frogs now are assigned to the 1,4-disubstituted quinolizidine class. For many of these, FTIR data are not yet available. Thus, structural and stereochemical assignments to this class, and the proposed 4,10Z configuration, should be considered tentative for many of these alkaloids. A 4,6-disubstituted quinolizidine class, considered likely by analogy to the... 

Precoccinelline (193C) and related tricyclic alkaloids have been detected only rarely in dendrobatid frogs and bufonid toads. Precoccinelline is a minor alkaloid in one Central American population of Dendrobates aura-tus 31), but it was a major alkaloid in an introduced population of D. 

Fig. 18. Alkaloids of the cyclopentaf/ilquinolizidine class from the dendrobatid frog, Minyobates bombetes. The structure of 251F was determined by nuclear magnetic resonance spectroscopy (/52), but the absolute configuration of 2S1F is unknown. The other structures are tentative and are based primarily on analogy and mass spectra.

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

In dendrobatid frogs, pyrrolidines have been detected only in certain populations of Dendrobates histrionicus and Dendrobates pumilio (/). Pyrrolidine trans-iSH is the only pyrrolidine to occur as a major alkaloid, and it appears only in the most northern populations of Dendrobates histrionicus. In nondendrobatid frogs, 2,5-disubstituted pyrrolidines have not been detected. 

Simple piperidines occur only rarely in amphibians thus far they have been found only in dendrobatids. As yet, the structure of only one piperidine from a dendrobatid frog has been firmly established 87). This is piperidine 241D, whose structure, determined to be a cw,c/s-2-methyl-6-n-nonyl-4-hydroxypiperidine by nuclear magnetic resonance spectroscopy, is shown in Fig. 21. A congener (255) which appears to have a keto group in the nonyl side chain also occurs in the same dendrobatid frog 87). Two other alkaloids from dendrobatid frogs appear to be 2,6-disubstituted... 

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