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.

Marine natural products

“…Structure–activity exploration of 2-aminoalkan-3-ols clavaminol A and xestoaminol C (as cytotoxins), 690 the cadiolide scaffold (as antibacterials), 691 tiruchanduramine (α/β-glucosidase inhibitors) 692 and meridianins and pulmonarins (against plant diseases) 693,694 have been reported. Virtual screening, followed by bioassay, identified the meridianins as also being GSK3β inhibitors.…”