Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2

Shelly Gapil Tiamas (1, 2) , Florian Daressy (1, 3) , Alma Abou Samra (1) , Jérôme Bignon (1) , Vincent Steinmetz (1) , Marc Litaudon (1) , Christophe Fourneau (4) , Kok Hoong Leong (2) , Azhar Ariffin (2) , Khalijah Awang (2) , Sandy Desrat (1) , Fanny Roussi (1)

1 ICSN - Institut de Chimie des Substances Naturelles
2 UM - University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie]
3 IGR - Institut Gustave Roussy
4 BioCIS - Biomolécules : Conception, Isolement, Synthèse

A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involve dabio-inspired Diels-Aldercycloaddition,followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1andBcl-2 proteins. In this series of cyclohexenyl chalcone analogues,six compounds behaved as dua lBcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1andBcl-2.The most potent compounds evaluated on A549 and MCF7cancer cell lines showed moderate cytotoxicities

Domaines: Chimie organique

Shelly Gapil Tiamas, Florian Daressy, Alma Abou Samra, Jérôme Bignon, Vincent Steinmetz, et al.. Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2. Bioorganic and Medicinal Chemistry Letters, 2020, 30, pp.127003. ⟨10.1016/j.bmcl.2020.127003⟩. ⟨hal-02483122⟩