2. Academic Validation
  3. Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2

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

  • Bioorg Med Chem Lett. 2020 Apr 1;30(7):127003. doi: 10.1016/j.bmcl.2020.127003.
Shelly Gapil Tiamas 1,  Florian Daressy 2,  Alma Abou Samra 3,  Jérome Bignon 3,  Vincent Steinmetz 3,  Marc Litaudon 3,  Christophe Fourneau 4,  Kok Hoong Leong 5,  Azhar Ariffin 6,  Khalijah Awang 6,  Sandy Desrat 7,  Fanny Roussi 8
Affiliations

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: [email protected].
  • 8 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France. Electronic address: [email protected].
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.

Keywords

Carboxamide; Diels-Alder; Mcl-1; Natural product; Pro-apoptotic.

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