Pumiliotoxin-A class

Free base (contains small amount of the C-11 epimer) (c 1.6, CHCI3) Mo -s.r 

Analysis of the nuclear magnetic resonance spectra had now provided the long sought key to the structures of pumiliotoxin A and B. Comparison 

Boronate and dimethylsilanate derivatives form very readily from pumiliotoxin B. Indeed, during gas chromatography on OV-1 columns, a portion of pumiliotoxin B was often converted to a dimethylsilanate, thus leading to the incorrect postulate that three dendrobatid alkaloids 379,381 and 395 were present (80). All of these were subsequently shown to be artefacts representing dimethylsilanates formed from pumiliotoxin B, a dihydropumiliotoxin B and an alkaloid now designated pumiliotoxin 339, Most of the compounds of the pumiliotoxin-A and allopumiliotoxin-A class have not been isolated in sufficient quantity or purity to allow nuclear 

Properties of pumiliotoxin A, B and 251D and other alkaloids of the pumiliotoxin-A class are reported below in the usual format empirical formulas which are based only on analogy and chemical and chromatographic properties and which have not been confirmed by high resolution mass spectrometry are in quotation marks. Certain trivial names employed earlier (80) are no longer used now that the structures of these alkaloids are better understood. 

The pumiliotoxin-A class of alkaloids with a major fragment ion at m/z 166 is widely distributed in frogs of the genus Dendrabates occurring in 14 of the 20 species in Table 22. The allopumiliotoxin-A subclass with a major fragment ion at m/z 182 occurs in 16 of the 20 species in Table 22. 

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Extracts from skins of the neotropical frog Dendrobates tricolor from Ecuador have given the alkaloid 8-hydroxy-6-(2-methylhexylidene)azabicyclo[4.3.0]non-ane (4), the structure and absolute configuration of which have been determined by X-ray crystallography of the hydrochloride salt. This alkaloid is the first structurally defined member of the pumiliotoxin A class of dendrobatid alkaloids. Spectroscopic studies (m.s. and n.m.r.) have allowed the formulation of the... 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

Once the structure of pumiliotoxin 25ID was known from crystal structure analysis, the structures of a number of other alkaloids of the pumiliotoxin A class were derived from mass spectra and NMR spectra (see e.g., Fig. 15). A problem still remains in assigning the stereoconfigurations of the hydroxyl groups in the long side chains. This kind of problem could be easily resolved by crystallography, if it were possible to grow a crystal. 

Most amphibian alkaloids are not as complex in structure as the steroidal batrachotoxins and samandarines. Of the 300 known amphibian alkaloids, most have been characterized from the skin extracts of frogs of the family Dendrobatidae and, hence, have been referred to as dendrobatid alkaloids. The major bicyclic classes of dendrobatid alkaloids are the histrionicotox-ins, decahydroquinolines, and pumiliotoxin-A class. Because of the presence of a piperidine ring in most dendrobatid alkaloids, they also have been referred to as piperidine-based alkaloids. 

Decahydroquinolines have relatively low toxicities, and for this reason and, more importantly, to avoid confusion with the pumiliotoxin-A class of alkaloids, the name pumiliotoxin C has been replaced with the name decahydroquinoline c/i-195A. Decahydroquinoline cw-195A at a subcutaneous dose of 100 /Ltg in a mouse causes difficulties in locomotor activity... 

Certain alkaloids of the pumiliotoxin A class isolated from dendrobatid skin extracts appear to be artifacts formed by rearrangement of the side chain allylic C-15 alcohol, or by reaction with methanol at the same allylic center (95). These are shown in Fig. 8. 

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. 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).

Optical rotations of the pumiliotoxin-A class alkaloids are reported in Table V. The mass spectra have been reported in detail and summarized... 

In summary, pumiliotoxin B and congeners now appear to represent another class of alkaloids that modulate the function of voltage-dependent sodium channels. They are valuable research tools, and perhaps models, for the development of new myotonic or cardiotonic agents. Direct effects of pumiliotoxin-A class alkaloids on calcium translocation, as originally proposed (99), still remain a possibility for further pharmacological study. 

In summary, the pumiliotoxin-A class alkaloids are unique to certain genera from four different families of amphibians. Pumiliotoxins and allo-pumiliotoxins often occur together. Homopumiliotoxins occur much less often. The unique and complex structures and the phylogenetic distribution of pumiliotoxin-A class alkaloids argue for the independent evolutionary development of a complex suite of biosynthetic enzymes. The branched-chain structures of the pumiliotoxin-A class also suggest the incorporation of isoprene units, unlike the preponderance of bicyclic den-drobatid alkaloids, which appear to be derived from straight-chain precursors. 

Two classes of simple indolizidines have been characterized from amphibians. These are in addition to the more complex pumiliotoxin-A class of indolizidines where 8-hydroxy, 8-methyl, and 6-alkylidene substituents are present in the indolizidine ring (see Section III,C). The simple indolizidines are either 3,5- or 5,8-disubstituted. However, the existence of 3- or 5-monosubstituted indolizidines also has been postulated. 

New synthetic methods and strategies for the total syntheses of pumiliotoxin A class alkaloids 99YGK981. 

Development of New Synthetic Methods and Strategies for the Total Syntheses of Pumiliotoxin A Class Alkaloids. 

Pumiliotoxin B, a representative member of the pumiliotoxin-A class of alkaloids potentiates both direct and indirect evoked contractions of striated muscle 24, 26,183). In addition, pumiliotoxin B prolongs muscle contraction / vide infra). The potentiation of muscle contracture appears to... 

Structure-activity correlations for pumiliotoxin-A class alkaloids have not been delineated because of the limited supplies available from nature. Pumiliotoxin B is more active in potentiating frog muscle contraction than is pumiliotoxin A, which in turn is much more active than pumiliotoxin 251D (cited in 24). Thus, hydroxyl groups in the side chain appear important to at least one biological activity of this class of alkaloids. 

Table 21. Effects of Alkaloids of the Pumiliotoxin-A Class on Biological Systems...

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