The Desigen,Synthesis & Biological Evaluation Of Novel Inhibitors Of The Anti-apoptotic Bcl-2 Protein

Apoptosis isessential cellular process in the development and homeostasis of multicellular organisms. Defects in apoptosis pathways can promote cancer cell survival and also confer resistance to antineoplastic therapy. Over expression of anti-apoptotic Bcl2 family proteins in many types of human cancer has been associated with chemotherapy resistance. Preclinical studies have shown that agents targeting antiapoptotic Bcl-2 protein have preclinical activity as single agents or in combination with other antineoplastic agents. Bcl-2 is a promising molecular target for the design of a novel class of anticancer drugs aimed to overcome resistance of the cancer cell to apoptosis.A structure based approach was employed to design novel small molecule anti-apoptotic Bcl-2 inhibitors in an attempt to understand the basic pharmacophore required for Bcl-2 inhibitory activity based on the lead compound 5-(1H-indol-3-yl)-N-(2-nitrophenyl)-1,3,4-oxadiazole-2-amine (6a) that previously obtained from virtual screening that found to be two fold less potent than gossypol in ELISA binding assay .