Towards the next generation of dual Bcl-2/Bcl-xL inhibitors
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- 作者：Jeffrey G. Varnes ; Jeffrey.Varnes@Astrazeneca.com" class="auth_mail ; Thomas Gero ; Shan Huang ; R. Bruce Diebold ; Claude Ogoe ; Paul T. Grover ; Mei Su ; Prasenjit Mukherjee ; Jamal Carlos Saeh ; Terry MacIntyre ; Galina Repik ; Keith Dillman ; Kate Byth ; Daniel John Russell ; Stephanos Ioannidis
- 关键词：Bcl-2 ; Bcl-xL ; Navitoclax ; B-cell lymphoma ; Apoptosis
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：15 July 2014
- 年：2014
- 卷：24
- 期：14
- 页码：3026-3033
- 全文大小：1452 K
文摘
Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL 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 RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.