Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues. Issue 41 (1st October 2021)

• Record Type: Journal Article
• Authors: Paysant, Hippolyte; Hedir, Siham; Justaud, Frédéric; Weiswald, Louis Bastien; El Dine, Assaad Nasr; Soulieman, Ali; Hachem, Ali; Elie, Nicolas; Brotin, Emilie; Denoyelle, Christophe; Bignon, Jérôme; Roussi, Fanny; Jouanne, Marie; Tasseau, Olivier; Roisnel, Thierry; Voisin-Chiret, Anne Sophie; Grée, René; Levoin, Nicolas; Poulain, Laurent
• Is Part Of: Organic & biomolecular chemistry. Volume 19:Issue 41(2021)
• Page Start: 8968
• Page End: 8987
• Publication Date: 2021-10-01
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d1ob01521d
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : This paper describes the synthesis and biological evaluation of new inhibitors of anti-apoptotic proteins towards novel anti-cancer agents. Abstract : In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-xL /Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure–activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-xL .