Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols. (26th April 2018)

• Record Type: Journal Article
• Authors: Bourkhis, Maroua; Gaspard, Hafida; Rullière, Pauline; de Almeida, Diana K. C.; Listunov, Dymytrii; Joly, Etienne; Abderrahim, Raoudha; de Mattos, Marcos C.; de Oliveira, Maria C. F.; Maraval, Valérie; Chauvin, Remi; Génisson, Yves
• Is Part Of: ChemMedChem. Volume 13:Number 11(2018)
• Page Start: 1124
• Page End: 1130
• Publication Date: 2018-04-26
• Subjects: alkynols -- asymmetric synthesis -- cytotoxicity -- enzymatic kinetic resolution -- marine lipids -- polyacetylenes; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800118
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Show some spine in fighting cancer : In two bioinspired lipidic series based on the terminal DAC and BAC pharmacophores, dramatic effects of lipid chain length on antitumor cytotoxicity are described. A C17 –C18 carbon backbone was found to be optimal, affording a 700‐fold enhancement in potency versus a reference natural product, with an IC50 value of 15 nm for the most active enantiomer of a BAC derivative.