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 C to C backbones. Enantiomerically enriched samples were prepared by asymmetric synthesis of the optimal C DAC and C BAC derivatives. Samples with upgraded enantiomeric purity were alternatively produced by enzymatic kinetic resolution. Eutomers possessing the S configuration displayed cytotoxicity IC values as low as 15 nm against HCT116 cancer cells, the highest level of activity reached to date in this series.
A recently proposed "ethynylogation" pharmacomodulation approach, first envisaged in the series of anticancer lipidic dialkynylcarbinols (DACs) H-C≡C-CH(OH)-C≡C-R at the levels of the H-C⋮ and ⋮C-R bonds for R = n-C 12 H 25 , is completed here at the level of the (HO)C-H bond. The sodevised mono-lipidic trialkynylcarbinol (TAC) target (HC≡C) 2 C(OH)-C≡CR and its bis-lipidic counterpart HC≡C-C(OH)(C≡CR) 2 were synthesized in 4 steps with 33 % and 23 % overall yield, respectively. Their antitumor cytotoxicity has been evaluated towards HCT116 cells: while the latter doubly lipidic TAC is totally inactive (IC 50 > 120 µM), the former DAC-ethynylogous TAC still exhibits a significant toxicity with an IC 50 of 40 µM.
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