A plug and play approach to structural variations of bio-inspired anticancer lipidic phenyl dialkynylcarbinols

Phenyl dialkynylcarbinols (PACs) are analogues of natural acetylenic lipids acting on human cells as cytotoxic prodrugs enantiospecifically bioactivated by HSD17B11. Here, we report a highly convergent and modular synthetic strategy to accelerate the exploration of their anticancer structure-activity relationships. Late-stage PAC assembly was achieved by Pd/Cu-catalysed coupling of three chiral alkynylcarbinol warheads, racemic or enantioenriched, with various functionalised lipidic aryl iodides. The added value of this methodology to directly access enantioenriched PAC analogues from an enzymatically resolved alkynylcarbinol precursor was also demonstrated. A total of 22 new compounds were prepared, including two butadiynylcarbinol congeners, with IC₅₀ values as low as 0.13 μM in HCT116 cancer cells. Enantiomeric comparisons confirmed strong eudismic ratios in this series. Genetic inactivation of HSD17B11 in U2OS cells demonstrated its key role in the cytotoxicity of most compounds, while 1,2,3-triazolyl allenyl alkynylcarbinols emerged as particularly promising, combining a novel chemotype, a potent activity, and an alternative mechanism of action.