Enantioselective Synthesis of Clavaminol A, Xestoaminol C and their Stereoisomers Exhibiting Cytotoxic Activity

Abstract

The simple preparation of the natural sphingoid bases possessing cytotoxic activity - the marine drugs Clavaminol A and Xestoaminol C and all their unnatural stereoisomers - in high enantiomeric purity (ca. 95 % of major enantiomer) was described. The individual enantiomers were obtained by the utilization of asymmetric Henry reaction. The diastereomers of target compounds were separated by column chromatography after transformation into corresponding 2-phenyloxazoline derivatives. The individual stereoisomers of Clavaminol A and Xestoaminol C were evaluated for antiproliferative activity in cancer cell lines (A-549; Jurkat; SH-SY5Y, MG-63). From the obtained IC50 values is obvious, that the stereoisomers of Xestoaminol C are more potent inhibitors of cell proliferation than the stereoisomers of Clavaminol A. Further, it was found, that stereoisomers with syn-configuration exhibited larger antiproliferative effects in comparison with the stereoisomers having anti-configuration, in both sphingoid bases. Nevertheless, the values of IC50 found for individual enantiomers in each of the enantiomeric pairs are rather comparable implying a possibility of using racemic mixtures for induction of cytotoxicity.