Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins

We report herein a new class of small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound, 7, binds to Bcl-2, Bcl-xL, and Mcl-1 proteins with K_i of 110, 638, and 150 nM, respectively. Compound 7 is highly effective in induction of cell death in breast cancer cells with high levels of Bcl-2, Bcl-xL, and Mcl-1 proteins and represents a promising lead compound for the design of new anticancer drugs. Apoptosis, or programmed cell death, is a critical cell process in normal development and homeostasis of multicellular organisms. Inappropriate regulation of apoptosis has been implicated in many human diseases, including cancer.^1-3 Targeting critical apoptosis regulators is an attractive therapeutic approach for the development of new classes of therapies for the treatment of cancer and other human diseases.¹ The Bcl-2^a family proteins are a class of central arbiters of apoptosis and consist of antiapoptotic members such as Bcl-2, Bcl-xL, and Mcl-1 and proapoptotic members such as Bim, Bid, Bak, and Bax.^4-7 The antiapoptotic proteins in the Bcl-2 family are overexpressed in many cancer cell lines and human cancer tissues. This overexpression protects cancer cells from the induction of apoptosis by current anticancer therapies and plays a role in the failure of conventional anticancer drugs.^4-7 Consequently, these antideath Bcl-2 proteins are considered to be promising molecular targets for the design of novel anticancer drugs.