Bufadienolides, structures

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). 

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. 

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... 

The cardioactive compounds from Bryophyllum species are bufadienolides with potent cytotoxic activity (Yamagishi et al, 1989). Bryophyllin B (35) (Fig. 24.9) from Bryophyllum pinnatum possesses an unusual orthoacetate-containing structure this compound has an ED50 of less than 80 ng/ml in the KB cell culture system (Yamagishi et al, 1989). 

Cardenolide structure is closely related to bufadienolides, but these 23C steroids possess a butenolide ring located at C17. As potent cardiotonics, they are widely distributed in plants mostly as glycosides. Digitoxigenin is a typical example of cardenolides. Besides, they are either toxins or insect deterrents. 

Toad extract, obtained from the secretions of the salivary and skin glands of Chinese toads, is commonly used in Chinese medicine. It contains bufotenine and a series of bufadienolides that are structurally similar to cardiac glycosides [119 ]. 

Recent studies on Asclepias curassavica [197], and Bersama abyssinica [198, 199] have shown that bufadienolides and cardenolides are cytotoxic and that hellebrigenin 3-acetate (XLIX) inhibits W 256 at 8 mg/kg. Structure-activity relationship studies on bufadienolides and cardenolides have failed to reveal the structural features required for activity [194]. 

Earlier, some of the same considerations had led me in 1957 to initiate a study of amphibian venoms of the steroidal bufadienolide (6) type as potential sources of new antineoplastic substances. Eventually we found that some of the toad venom bufadienolides such as marinobufagin significantly inhibit growth of the National Cancer Institute s KB cell line derived from a human nasopharynx carcinoma and lead to a curative response with the murine Ehrlich ascites system (7). However, the therapeutic indices were unattractive for further development. So the effort was extended in 1965-66, as Just noted, to encompass a geographically far-reaching area (Asia, Africa, Australia etc.) and an extensive research program to evaluate marine invertebrates and arthropods for structurally unique and useful anticancer constituents. Subsequently we isolated the first such invertebrate antineoplastic constituents (8-12). Meanwhile, our early expectations have been abundantly realized and the discovery of the bryostatins provides a splendid illustration. 

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