Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues

Abstract

In the cancer research area, 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...

Synthesis and biological evaluation of FJ-809, a compound originally described as MIM1 and an inhibitor of the anti-apoptotic protein Mcl-1

“…Here, we showed (Fig. 4) in this model that MIM1 ( 2 ) exhibits a modest activity on IGROV1-R10 cells at 10 μM in combination with ABT-737, as previously described, 9 suggesting its Mcl-1 inhibitory properties, as expected. Cell detachment and nuclear condensations or fragmentations are observed after a 24 h exposure to MIM1 ( 2) (13% at 10 μM, Fig.…”

“…As we already described, 9 the binding modes of FJ-809 and MIM1 are very similar (Fig. 6), with conserved interaction features (van der Waals contacts for the core, hydrogen bonds for the triphenol).…”

“…All these molecules have spectral and analytical data (see the Experimental section and the ESI†) consistent with their structure. Most informative are the comparisons of the NMR data of 1 ( FJ-809 ) with those (already reported) 9 of the MIM1 molecule 2 . The 1 H NMR spectrum of a 1 : 1 mixture of both compounds (Fig.…”

“…We compared the activity of the two molecules 1 and 2 on IGROV1-R10 ovarian cancer cells, whose survival is dependent on both Bcl-x L and Mcl-1, as described previously. 9 In these cells, the concomitant inhibition of these two anti-apoptotic proteins leads to massive apoptotic cell death. It thus constitutes a relevant model in the context of Bcl-x L /Mcl-1 inhibitor screening studies.…”

“…Then in vitro and in cellulo biological experiments, combined with extensive molecular modelling studies, allowed us to propose preliminary structure–activity relationships for these series of molecules. 9…”