Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols

Abstract

In line with a recent study of the pharmacological potential of bioinspired synthetic acetylenic lipids, after identification of the terminal dialkynylcarbinol (DAC) and butadiynyl alkynylcarbinol (BAC) moieties as functional antitumor pharmacophoric units, this work specifically addresses the issue of carbon backbone length. A systematic variation of the aliphatic chain length was thus carried out in both the DAC and BAC series. The critical impact of the length of the lipidic skeleton was first confirmed in the racemic series, with the highest cytotoxic activity observed for C₁₇ to C₁₈ backbones. Enantiomerically enriched samples were prepared by asymmetric synthesis of the optimal C₁₈ DAC and C₁₇ BAC derivatives. Samples with upgraded enantiomeric purity were alternatively produced by enzymatic kinetic resolution. Eutomers possessing the S configuration displayed cytotoxicity IC₅₀ values as low as 15 nm against HCT116 cancer cells, the highest level of activity reached to date in this series.

Keywords: alkynols; asymmetric synthesis; cytotoxicity; enzymatic kinetic resolution; marine lipids; polyacetylenes.