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

Gapil Tiamas S 1 , Daressy F 2 , Abou Samra A 3 , Bignon J 3 , Steinmetz V 3 , Litaudon M 3 Show all authors , Fourneau C 4 , Hoong Leong K 5 , Ariffin A 6 , Awang K 6 , Desrat S 7 , Roussi F 8

Affiliations 

  • 1 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France; Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • 2 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France; Université Paris-Saclay, UMR CNRS 8126, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805 Villejuif Cedex, France
  • 3 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France
  • 4 Université Paris-Saclay, BioCIS, Faculté de Pharmacie de Châtenay-Malabry, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
  • 5 Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • 6 Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • 7 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France. Electronic address: sandy.desrat@cnrs.fr
  • 8 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France. Electronic address: fanny.roussi@cnrs.fr
Bioorg Med Chem Lett, 2020 04 01;30(7):127003.
PMID: 32035700 DOI: 10.1016/j.bmcl.2020.127003

Abstract

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 sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.

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