Synthesis and biological evaluation of , a compound originally described as and an inhibitor of the anti-apoptotic protein Mcl-1

• Published in: New journal of chemistry Vol. 46; no. 19; pp. 9119 - 9127
• Main Authors: Justaud, Frédéric, Paysant, Hippolyte, Weiswald, Louis Bastien, Jebahi, Abdelghani, Jouanne, Marie, Elie, Nicolas, Voisin-Chiret, Anne Sophie, Roisnel, Thierry, Orione, Clément, Levoin, Nicolas, Poulain, Laurent, Grée, René
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 16.05.2022
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; BCL-2; SMALL-MOLECULE; ONE-POT; THIOSEMICARBAZONE; CANCER; DERIVATIVES; DISCOVERY
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d1nj05987d

The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research. One of the very first reported inhibitors of Mcl-1 was the MIM1 molecule, but we have recently demonstrated that the structure of this compound had to be revised from 2 to the derivative 1 ( FJ-809 ). In this paper we first develop a strategy to unambiguously prepare molecules such as 1 with a thiazol-3(2 H )-yl)imino core, instead of the [2(3H)-thiazolylidene]hydrazine previously found in MIM1 ( 2 ). Next a series of biological studies have been performed on 1 , using IGROV1-R10 ovarian cancer cells as models, and they have been complemented by fluorescence polarisation assays. These studies demonstrated that the new compound FJ-809 (1) was devoid of any significant activity on Mcl-1, in contrast to 2 . Then molecular modelling and molecular dynamics studies have been performed in order to elucidate the differences between FJ-809 and MIM1 in their interaction with the Mcl-1 protein. The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research.