Bufadienolides

Catalytic reduction in the presence of base followed by sodium borohydride reduction of the 14-hydroxy-A -3,17-dione (1) gave the 3a-hydroxy-5)8-derivative 

Austin, Advances in Steroid Biochemistry and Pharmacology, Vol. 1, Ed., M. H. Briggs, Academic Press, London, 1970. 

Bu OH xiii, TsOH-MeOH xiv. POCI3-DMF xv, NaOH-EtOH-H O xvi. BrCHj COjEt-Zn-DMF xvii, HCl-MeOH-HjO xviii, TsOH-py xiv, DMP XX, Al203-Et20 xxi, NBS xxii, Basic AI2O3 xxiii, LiAIH4-Et20. 

Two short syntheses of 14a-bufadienolides have been described in which either of the aldehyde derivatives (12) or (15) are treated with carbomethoxy-methylenediethylphosphonate to give the unsaturated esters (13) and (16). The former was then cyclised directly to the bufadienolide (14) whilst (16) was converted to the free aldehyde (17) before cyclisation. The aldehyde derivatives (12) and (15) are readily prepared by short reaction sequences involving reaction of the dimethyl acetal (18) with either methoxymethylenetriphenylphosphorane or dimethylsulphonium methylide. Use of this latter route gives the spiro-epoxide 

Radscheit, U. Stache, W. Haede, W. Fritsch, and H. Ruschig, Tetrahedron Letters, 1969, 3029. 

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When used at room temperature in the presence of an active platinum catalyst in an inert solvent, e.g., acetone or ethyl acetate, oxygen will oxidize nonhindered, saturated hydroxyl groups and exposed allylic alcohols. This reagent has found extensive use in sugar chemistry and is particularly suited for the selective oxidation of either 3a- or 3j -alcohols of steroids. Other hydroxyl groups on the steroid skeleton are much less sensitive to oxidation. As a result, this reaction has been used extensively in research on polyhydroxy cardiac-active principles, e.g., the cardenolides and bufadienolides, where the 3-hydroxyl group is easily oxidized without extensive oxidation or dehydration of other hydroxyl groups. The ordinarily difficult selective oxidation of the... 

Na+/K+-ATPase. Figure 2 Specific Inhibitors of Na+/K+-ATPase. (a) Endogenous cardiac glycosides identified in mammals. Substances with a 5-membered lactone at position C17 of the steroid moiety are referred to as cardenolides, those with a 6-membered lactone as bufadienolides. (b) Palytoxin (C P NsO ) produced by corals of the genus Palythoa. 

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. 

Toad bufadienolides occur not only by themselves but also in a conjugated form, sulfates, dicarboxylic esters and amino acid-dicarboxylic acid esters have all been reported (Steyn and van Heerden 1998). Because of the activity of the bufadienolides in inhibiting active monovalent cation transporters, it is suggested that these compounds have a role in maintaining sodium homeostasis in toads that migrate between fresh and salt water environments (Flier, I idwards, Daly and Myers 1980). 

A novel substance with a bufadienolide-related chemical structure has been isolated from B. marinus skin. This substance is 3P-hydroxy-ll, 12-seco-5p, 14P-bufa-20, 22-dienolide-l 1, 14-olides-12oic acid (called marinoic acid) and shows the Na+/K+-ATPase inhibitory activity characteristic of the bufadienolides (Matsukawa, Akizawa, Morris, Butler Jr and Yoshioka 1996). 

Fig. 39.1 Bufadienolides identified from the a) skin and b) eggs of B. marinus...

AMzawa, T., Mukai, T., Matsukawa, M., Yoshioka, M., Morris, J. F. and Butler Jr, V. P. (1994) Structures of novel bufadienolides in the eggs of a toad, Bufo marinus. Chem. Pharm. Bull. 42, 754-756. 

Brizzi, R., Delfino, G. and Pellegrini, R. (2002) Specialized mucous glands and their possible adaptive role in the males of some species of Rana (Amphibia, Anura). J. Morph. 254, 328-341. Chen, C. and Osuch, M. V. (1969) Biosynthesis of bufadienolides - 3Bhydroxycholonates as precursors in Bufo marinus bufadienolides synthesis. Biochem. Pharmacol. 18, 1797-1802. Chivers, D. P. and Smith, R. J. F. (1998) Chemical alarm signalling in aquatic predator-prey systems a review and prospectus. Ecosci. 5, 338-352. 

This direct synthesis of steroidal pyrones should make a variety of structures related to the lucibufagins (as well as to the toad-derived bufadienolides) readily available for biological investigation for the first time. How the insects themselves manage to obtain their defensive pregnanes and steroidal pyrones remains a mystery, since insects are generally considered to lack the enzymatic machinery essential for steroid biosynthesis (19). In fact, we do not yet know whether these insect defensive steroids are produced de novo or whether they are derived... 

Botha, C.J., Van der Lugt, J.J., Erasmus, G.L., Kellerman, T.S., Schultz, R.A. and Vleggaar, R. (1998). Krimpsiekte, a paretic condition of small stock poisoned by bufadienolide-containing plants of the Crassulaceae in South Africa, in Garland, T. and Barr, A.C., Eds., Toxic plants and other natural toxicants, CAB International, Wallingford, pp. 407%-12. 

In the field of the components of the venom from toads, he studied the venom of most South American species of the genus Bufo, determining with several coworkers, and also in collaboration with T. Reichstein (University of Basel), their composition in regard to bufadienolides, bioge-netic amines, and alkaloid-like compounds. 

The bufadienolides occur in plants as well as animals, but only in plants are they in the form of glycosides. Their 3-hydroxyl group is attached lo glucose, rhamnose, or thevetosc. Hellebrigenin (Fig. 2). which is also known as bufotalidin. occurs in the rhizomes of the Christmas rose and other Helleborus species in the form of a rhamnoside. Bufadienolides have so far been found in plants in only two families, the buttercup and the lily family. 

Krenn L and Kopp B (1998) Bufadienolides from animal and plant tissue. Phytochemistry 48, 1 -29. 

Steyn PS and van Heerden FR (1998) Bufadienolides of plant and animal origin. Nat Prod Rep 15, 397-413. 

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