Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-Based High Throughput Screening Assay. 4. Structure–Activity Relationships of N-Al

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• 作者：William Kemnitzer ; John Drewe ; Songchun Jiang ; Hong Zhang ; Candace Crogan-Grundy ; Denis Labreque ; Monica Bubenick ; Giorgio Attardo ; Real Denis ; Serge Lamothe ; Henriette Gourdeau ; Ben Tseng ; Shailaja K
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：417 - 423
• 全文大小：141K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

In our continuing effort to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the structure−activity relationship (SAR) of alkyl substituted pyrrole fused at the 7,8-positions. A methyl group substituted at the nitrogen in the 7-position of the pyrrole ring led to a series of potent apoptosis inducers with potency in the low nanomolar range. These compounds were also found to be low nanomolar or subnanomolar inhibitors of cell growth, and they inhibited tubulin polymerization, indicating that methylation of the 7-position nitrogen does not change the mechanism of action of these chromenes. Compound 2d was identified as a highly potent apoptosis inducer with an EC₅₀ value of 2 nM and a highly potent inhibitor of cell growth with a GI₅₀ value of 0.3 nM in T47D cells.