Enantioselective synthesis of clavepictine analogues and evaluation of their cytotoxic activity

Six analogues (labeled 27 to 32) of a cytotoxic alkaloid isolated from the tunicate Clavelina picta were synthesized from an acyl oxazolidine. The absolute stereochemistry of the targeted analogues derived from (R)-phenyl glycinol and the relative stereochemistries of three of the four stereocentres present in the molecule were set up by stereocontrolled additions to transient iminium ions. The main features of this synthesis include (i) a high level of stereocontrol for all the steps involving the arrangement of relative stereochemistries, (ii) a divergent introduction of the side chain at the end of the synthesis, allowing the easy preparation of the different analogues, and (iii) an original step involving an intramolecular alkylation of an aminonitrile moiety that enabled the efficient construction of the quinolizidine core to take place. Together with the cytotoxic activities of the six analogues, those of three reference compounds (etoposide, adriamycin and irinothecan) were determined by means of the colorimetric MTT assay on four human-cancer cell lines. Compound 31 had a cytotoxic effect on the four human-cancer cell lines in dose ranges similar to etoposide and irinothecan. Compound 30 also had a significant cytotoxic effect on all four of the human-cancer cell lines under study, but these activities were weaker than those induced by compound 31. Compound 29 had a significant cytotoxic effect on three of the four human-cancer cell lines, and compounds 27, 28 and 32 had no cytotoxic effect (except compound 27 with respect to the A549 model at the highest dose) on the four human models under study. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).