Isabelle Fabing

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.

Considering the importance of organic functionalization of MOFs, we here report a simple, tunable and efficient one-step post-modification procedure for introducing amino and carboxylic groups into the mesoporous metal–organic framework Al- and Cr-MIL-101-NH₂ based on its reaction with alkyl bromides. This procedure allows also access to polyfunctionalized MIL-101 decorated with both carboxylic and primary amino groups. Other chemical functions, such as alcohols and alkynes, were also successfully introduced by this method.

Considering the importance of organic functionalization of MOFs, we here report a simple, tunable and efficient one-step post-modification procedure for introducing amino and carboxylic groups into the mesoporous metal-organic framework Al- and Cr-MIL-101-NH2 based on its reaction with alkyl bromides. This procedure allows also access to polyfunctionnalized MIL-101 decorated with both carboxylic and primary amino groups. Other chemical functions, such as alcohols and alkynes, were also successfully introduced by this method.

Synthesis of natural (2Z)-Lachnophyllum methyl ester and (4Z)-Lachnophyllum lactone is reported. The developed routes enabled the first synthesis of non-natural analogs of these natural compounds. Biological activities of the series were evaluated.

Cr-MIL-101-NH ₂ (MOF1) has been used to encapsulate large amounts of copper sulfate and the resulting loaded material, Cu@MOF1, was successfully used to promote the CuAAC click reaction.