Towards the next generation of dual Bcl-2/Bcl-xL inhibitors

被引：15

作者：

Varnes, Jeffrey G. ^{[1
]}

Gero, Thomas ^{[1
]}

Huang, Shan ^{[1
]}

Diebold, R. Bruce ^{[1
]}

Ogoe, Claude ^{[1
]}

Grover, Paul T. ^{[1
]}

Su, Mei ^{[1
]}

Mukherjee, Prasenjit ^{[1
]}

Saeh, Jamal Carlos ^{[1
]}

MacIntyre, Terry ^{[1
]}

Repik, Galina ^{[1
]}

Dillman, Keith ^{[1
]}

Byth, Kate ^{[1
]}

Russell, Daniel John ^{[1
]}

Ioannidis, Stephanos ^{[1
]}

机构：

[1] AstraZeneca R&D Boston, Oncol Innovat Med Unit, Waltham, MA 02451 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 14期

关键词：

Bcl-2; Bcl-x(L); Navitoclax; B-cell lymphoma; Apoptosis; SELECTIVE BCL-2 INHIBITOR; DISCOVERY; POTENT; ANTAGONISTS; ABT-737;

D O I：

10.1016/j.bmcl.2014.05.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3026 / 3033

页数：8

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