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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Tiamas, Shelly Gapil^1,2  Daressy, Florian^1,3  Abou Samra, Alma¹  Bignon, Jerome¹  Steinmetz, Vincent¹  Litaudon, Marc¹  Fourneau, Christophe⁴  Leong, Kok Hoong⁵  Ariffin, Azhar²  Awang, Khalijah²  Desrat, Sandy¹  Roussi, Fanny¹ 

[1] Univ Paris Saclay, Inst Chim Subst Nat, CNRS, UPR 2301, F-91198 Gif Sur Yvette, France

[2] Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia

[3] Univ Paris Saclay, Inst Gustave Roussy, UMR CNRS 8126, 114 Rue Edouard Vaillany, F-94805 Villejuif, France

[4] Univ Paris Saclay, Fac Pharm Chatenay Malabry, BioCIS, 5 Rue Jean Baptiste Clement, F-92296 Chatenay Malabry, France

[5] Univ Malaya, Fac Med, Dept Pharm, Kuala Lumpur 50603, Malaysia

关键词: Natural product;    Diels-Alder;    Carboxamide;    Pro-apoptotic;    Mcl-1;   

DOI  :  10.1016/j.bmcl.2020.127003

来源: Elsevier

【 摘 要 】

A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited submicromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.

【 授权许可】

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