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

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 (3 r , 6 r ) pseudoasymmetric configuration to the natural product 3-dihydrodiscorhabdin C ( 5 ). Analogues incorporating increasingly bulky substitution at C-3 only retained cytotoxicity if they bore (3 s , 6 s )-configuration at the spiro-dienol moiety. A variety of fluorophore-labelled probes were prepared of which only a dansyl analogue ( 14 ) exhibited (modest) cytotoxicity. [ABSTRACT FROM AUTHOR]