Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-Based High-Throughput Screening Assay. 3. Structure-Activity Relationships of Fused Rings at the

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• 作者：William Kemnitzer ; John Drewe ; Songchun Jiang ; Hong Zhang ; Jianghong Zhao ; Candace Crogan-Grundy ; Lifen Xu ; Serge Lamothe ; Henriette Gourdeau ; Ré ; al Denis ; Ben Tseng ; Shailaja Kasibhatla ; Sui Xio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 14, 2007
• 年：2007
• 卷：50
• 期：12
• 页码：2858 - 2864
• 全文大小：118K
• 年卷期：v.50,no.12(June 14, 2007)
• ISSN：1520-4804

文摘

As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes asnovel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl groupwas found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were foundto inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not changethe mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC₅₀of 5 nM and a highly potent inhibitor of cell proliferation with a GI₅₀ of 8 nM in T47D cells.