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
  • 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.