Structure-Activity Relationship Studies of Phenanthridine-Based Bcl-XL Inhibitors

被引：123

作者：

Bernardo, Paul H. ^{[1
]}

Wan, Kah-Fei ^{[2
]}

Sivaraman, Thirunavukkarasu ^{[3
]}

Xu, Jin ^{[1
]}

Moore, Felicity K. ^{[1
]}

Hung, Alvin W. ^{[1
]}

Mok, Henry Y. K. ^{[3
]}

Yu, Victor C. ^{[2
]}

Chai, Christina L. L. ^{[1
]}

机构：

[1] ASTAR, Inst Chem & Engn Sci, Jurong Island 627833, Singapore

[2] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore

[3] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 21期

关键词：

D O I：

10.1021/jm8005433

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite their structural similarities, the natural products chelerythrine (5) and sanguinarine (6) target different binding sites on the pro-survival Bcl-X-L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X-L. and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC50 values.

引用

页码：6699 / 6710

页数：12

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