Towards the next generation of dual Bcl-2/Bcl-x(L) inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 14; pp. 3026 - 3033
• Main Authors: Varnes, Jeffrey G., Gero, Thomas, Huang, Shan, Diebold, R. Bruce, Ogoe, Claude, Grover, Paul T., Su, Mei, Mukherjee, Prasenjit, Saeh, Jamal Carlos, MacIntyre, Terry, Repik, Galina, Dillman, Keith, Byth, Kate, Russell, Daniel John, Ioannidis, Stephanos
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.07.2014
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Bcl-2; SELECTIVE BCL-2 INHIBITOR; POTENT; Navitoclax; ABT-737; Bcl-x(L); ANTAGONISTS; DISCOVERY; B-cell lymphoma; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.05.036

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-x(L) in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the R-S versus S-S sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately threefold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-x(L). (C) 2014 Elsevier Ltd. All rights reserved.