Allopumiliotoxins

SAM, samandarines BTX, batrachotoxins HTX, histrionicotoxins PTX, pumiliotoxins aPTX, allopumiliotoxins hPTX, homopumiliotoxins DHQ, 2,5-disubstituted decahydroquinolines 3,5-P, 3,5-d [substituted pyrrolizidines 3,5-1 and 5,8-1, disubstituted indolizidines 1,4-Q, 1,4-disubstituted quinolizidines Epi, epibatidine Pseudophry, pseudophrynamines. With the exception of 3,5-P and 3,5-1, these alkaloids are not known to occur in arthropods (see text). Histrionicotoxins may occur in Minyobates and Mantella, but the evidence is not conclusive. 

The basic hydrolysis of the 3-oxoperhydropyrrolo[l,2-c]oxazole 302 with KOH in ethanol followed by reaction with propargyl bromide 303 in presence of Hilnig s base in THF produced the derivative 304. This compound was further converted in a few steps to the natural product allopumiliotoxin 267A, 305 (Scheme 43) <1999JA6098, 2000JA6950>. 

Comins et al. <20010L469> achieved the synthesis of the same allopumiliotoxin 267A 215 by a stereoselective alkynylation of the appropriately substituted 4-MeO-pyridine 226. The C-6 side chain is introduced by an aldol condensation between an aldehyde and indolizidinone 227 (Equation 17). 

Table 2 Structure of pumilio- and allopumiliotoxins synthesized since 1995...

OH n-C3H7 Allopumiliotoxin 267A 1997JA6984, 1996JA9073, 2000JA6950, 20010L469... 

Cyclization of P-allenylamine systems to six-membered ring products has been observed recently. Cyclization of terminally substituted p-allenylamides with silver tetrafluoroborate produced lactam products (equation 137).267 The cyclization shown in equation (138) was used to generate the indolizidine ring system of allopumiliotoxin alkaloids.2676... 

Allenynes, reductive cyclization, 10, 516 Allocolchicine, via C-H functionalizations, 10, 162 Allocyathin, via Alder-ene reactions, 10, 592 (+)-Allopumiliotoxin 267A, via cyclization-hydrosilylation,... 

The alkaloids that appear to belong to the pumiliotoxin-A class are listed below as pumiliotoxins, allopumiliotoxins, or homopumiliotoxins. For many, the data do not yet allow formulation of a tentative structure. Also, it should be noted that some of the structures in Figs. 6, 7, and 9 deserve further study, particularly with regard to substituent configurations in side... 

Fig. 7. Structures of allopumiliotoxins. Absolute configurations are known for 267A, 339A, and 339B and are assumed to be the same for the others. All occur in dendrobatid frogs. Some also occur in ranid (Mantella), bufonid (Melanophryniscus), and myobatrachid (Pseudophryne) amphibians (73,73,8))-...

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).

Pumiliotoxin A (307A) and pumiliotoxin B (323A) are relatively toxic compounds causing death in mice at subcutaneous doses as low as 20 pig for pumiliotoxin B and 50 pig for pumiliotoxin A (see review in Ref. 5). Allopumiliotoxin 267A is less toxic, causing only locomotor difficulties at 40 pig per mouse (60). 

The effects of pumiliotoxin B on sodium channels appear to be due to interaction with a subdomain of the site at which batrachotoxin acts scorpion toxins and brevetoxin can potentiate the effects of pumiliotoxin B and of congeneric pumiliotoxins and allopumiliotoxins (102,112). Certain pumiliotoxin congeners appear to block sodium channel activation and may act as antagonists or reverse agonists (106). Structure-activity relationships with respect to stimulation of sodium flux and phosphoinositide breakdown have been studied (106). The nature of the side chain is critical to activity. For example, whereas pumiliotoxin B is one of the most potent of these alkaloids, its 15,16-erythro isomer has much lower activity (106,112). 

Pumiliotoxins and/or allopumiliotoxins are major alkaloids in most species of the dendrobatid genus Dendrobates (1). The exceptions are a few populations of D. pumilio, one population of D. auratus, all the populations of D. histrionicus except those north of or in the Rio San Juan drainage, and D. occultator and D. truncatus. In the dendrobatid genus Epipedobates, pumiliotoxins and/or allopumiliotoxins are major alkaloids in 4 of the 11 species examined, namely, E. erythromus, E. espinosai, E. silverstonei. 

Allergenic effects, allelochemicals, 60-61 Allopumiliotoxins occurrence, 223-224 spectral properties, 218-220 structures, 213, 215... 

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