Synthesis and biological studies on ovarian cancer cells of new heterocyclic molecules inspired by MIM1, an inhibitor of the anti-apoptotic protein Mcl-1

Abstract

Research on new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic in bioorganic and medicinal chemistry. MIM1 is a small molecule that was among the first reported inhibitors of the anti-apoptotic protein Mcl-1. We recently corrected its structure and developed a focused library of analogues to obtain new dual Bcl-x_L/Mcl-1 inhibitors as well as selective Mcl-1 inhibitors. All the corresponding molecules contained a triphenol core, established by molecular modelling as the key component to anchor these products to the binding site of these proteins. Thus, as a next step, we designed and synthesized novel analogues in which this labile core was replaced by a meta carboxylic acid. A focused library of such molecules was submitted to a set of in cellulo biological studies, which allowed new potent and selective inhibitors of Mcl-1 to be identified. Preliminary structure–activity relationships were elucidated, and molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the inhibition of the anti-apoptotic protein Mcl-1.