Exploration of the influence of spiro-dienone moiety on biological activity of the cytotoxic marine alkaloid discorhabdin P

Abstract

In order to clarify the importance of the C-3 carbonyl group to the cytotoxicity observed for discorhabdin marine alkaloids a number of semi-synthetic analogues of discorhabdin P were prepared. C-3 Reduction and acetylation typically resulted in a 4- to 10-fold reduction in cytotoxic potency (P388 cell line) compared to the corresponding keto parent compound. X-ray crystallography of a C-3 dienol derivative of discorhabdin P (6) allowed assignment of (3r, 6r) pseudoasymmetric configuration to the natural product 3-dihydrodiscorhabdin C (5). Analogues incorporating increasingly bulky substitution at C-3 only retained cytotoxicity if they bore (3s, 6s)-configuration at the spiro-dienol moiety. A variety of fluorophore-labelled probes were prepared of which only a dansyl analogue (14) exhibited (modest) cytotoxicity.