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 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.

From Natural to Artificial Antitumor Lipidic Alkynylcarbinols: Asymmetric Synthesis, Enzymatic Resolution, and Refined SARs

“…Systematic cytotoxicity assays against HCT116 cells showed that rac-20 and rac-20+1, with respective C 17 and C 18 carbon skeletons, are the most potent over the series. 65 These results are consistent with preliminary observations in the AAC series, where the shortening of the carbon skeleton from C 20 in the natural product 1 to C 17 in the artificial AAC 10 results in a five-fold increase in cytotoxicity (Table 1). 20 In the scalemic series, (R)-and (S)-20+1 were then prepared through the two-step method previously used for the synthesis of (R)-and (S)-20.…”

“…In the DAC racemic series, the length of the C 12 paraffinic chain of the reference rac-20 was increased up to C 16 in rac-20+4 and shortened down to C 9 in rac-20-3 (Scheme 17). 65…”

“…Variation of the lipidic chain length was also investigated in the BAC racemic series from the most potent C 19 BAC reference 54. 65 Samples of C 15 to C 21 rac-54x [x = +n -11= -4, -3, -2, -1, (0), +2] were prepared by addition of n-alkylbutadiynyllithiums of various length to TMS-propynal, followed by smooth protodesilylation with AgNO 3 (Scheme 19). The cytotoxicity of the six representatives was evaluated against the same HCT116 cells.…”

Fluorinated analogues of lipidic dialkynylcarbinol pharmacophores: synthesis and cytotoxicity in HCT116 cancer cells

“…The IC50 value of a racemic LAC sample is thus expected to be roughly two times higher than that of the corresponding eutomer: results in the racemic series are however relevant prior to optimization . We reported that the acetylated analogue (S)-2 displayed a cytotoxicity in HCT116 similar to that of (S)-1, probably due to in cellulo hydrolysis of the acetate moiety, releasing the free DAC [5]. In contrast, the O-methylated derivative 3 proved to be inactive (IC50 > 10 µM) [6].…”

Lipase-catalysed enantioselective kinetic resolution of rac-lipidic alkynylcarbinols and a C5 synthon thereof via a hydrolysis approach

“…and (S)-3 (84% e.e. ), embedding two conjugated triple bonds in the lipidic chain [5]. A different approach was considered for the enantioselective synthesis of the simple LAC (S)-4 (> 99% e.e.).…”