Design, synthesis and evaluation of novel Apogossypol derivatives targeting anti-apoptotic Bcl-2 family proteins

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Apogossypol, a semi-synthetic compound derived from the natural product Gossypol, possess anti-cancer activity by targeting anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-xL. Apogossypol retains most of cytotoxic activity against cancer cells but is much less toxic than Gossypol for normal cells because it lacks two reactive aldehyde functionalities. These observations make Apogossyol a better lead compound than Gossypol for further optimizations. In order to obtain compounds which have improved potency, stability and drug-like properties than Apogossypol, novel synthetic routes were designed to obtain novel derivatives. The resulting compounds are evaluated for their ability to bind in the BH3 binding groove of Bcl-xL, by using a combination of nuclear magnetic resonance (NMR) binding assays and in vitro displacement assays. Computer docking studies supported by the NMR data provide a detailed picture of the possible interaction mode of Apogossypol and its derivatives with Bcl-xL. Preliminary cell-based evaluations and in vivo studies with most promising compounds will be presented.