Description
Atropisomerism is a form of chirality that arises from hindered rotation around a bond resulting in rotational isomers that are non-superimposable mirror images (enantiomers). Even though atropisomerism is currently a point of contention in pharmaceutical pursuits since it can have an intrinsic effect on the biological activity of molecules, no one has purposely rigidified an atropisomeric axis as part of the drug design process. Biologically active scaffolds that display atropisomerism are ubiquitous throughout drug discovery. For example, various small molecule inhibitors of B-cell lymphoma 2 (Bcl- 2) family proteins contain one or more instances of atropisomeric axes. Bcl-2 is a member of a family of proteins that regulate cellular apoptosis. The intrinsic apoptotic pathway acts via the mitochondria and is dependent on several pro-and anti-apoptotic Bcl-2 proteins and is regulated by key protein-helical interactions. The expression of these proteins is tightly regulated and overexpression of these proteins is found throughout oncology, resulting in a large research effort towards Bcl-2 inhibition. We successfully developed a synthetic route towards atropisomerically stable analogs of a class of small molecule α-helix mimics that are known to inhibit Bcl-2 anti-apoptotic proteins but exist as interconverting atropisomers, with the hypothesis that such analogs will possess greater efficacy and selectivity. This work will allow for the study of biological implications of atropisomeric preorganization and the ability to access a variety of chemical modifications in order to study the effect of atropisomerism in other biologically relevant scaffolds.
