Design and Synthesis of α-Helix Mimetics Based on a Tris-Benzamide Scaffold to Target Bcl Proteins

摘要

Regulation of cell death relative to cell proliferation is crucial for tissue homeostasis, and any impairment in this process may lead to life-threatening diseases like cancer. Among numerous genes and proteins involving in apoptosis, members of a Bcl-2 family play a pivotal role in the control of cell death. The Bcl-2 family is divided into two groups, anti-apoptotic proteins like Bcl-2 and Bcl-x_L that inhibit programmed cell death, and pro-apoptotic proteins like Bak, Bad, and Bax that promote the process of apoptosis [1J. The formation of heterodimers between proand anti-apoptotic proteins regulates cell death since unbound pro-apoptotic proteins trigger the formation of pores in mitochondrial membrane, resulting in the release of cytochrome c, which in turn activates caspase cascade that ultimately leads to cell death. Since over-expression of anti-apoptotic proteins are commonly observed in many cancers, small molecules that can inhibit Bcl protein complex formation would be of high potential for cancer treatment.