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Article Dans Une Revue Journal of Medicinal Chemistry Année : 2023

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids

Isabelle Fabing
Valérie Maraval
Remi Chauvin

Résumé

A series of 25 chiral anti-cancer Lipidic AlkynylCarbinols (LACs) was devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting Phenyl-diAlkynylCarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC 50 down to 40 nM for resolved eutomers. A clickable probe allowed confirming the PACs prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 Short-chain Dehydrogenase/Reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin-proteasome system inhibition and apoptosis. Insights into the design of LAC prodrugs specifically bioactivated by HSD17B11 vs. its paralogue HSD17B13 were obtained. The HSD17B11/HSD17B13-dependent cytotoxicity of PACs was exploited to develop a cellular assay to identify specific inhibitors of these enzymes. A docking study was performed with the HSD17B11 AlphaFold model providing molecular basis of the SDR substrates mimicry by PACs. The safety profile of a representative PAC was established in mice.

Domaines

Chimie
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Dates et versions

hal-04274040 , version 1 (07-11-2023)

Identifiants

Citer

Margaux Bossuat, Pauline Rullière, Nadège Preuilh, Antonio Peixoto, Etienne Joly, et al.. Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids. Journal of Medicinal Chemistry, 2023, 66 (20), pp.13918-13945. ⟨10.1021/acs.jmedchem.3c00859⟩. ⟨hal-04274040⟩
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