Discovery of N-aryl-9-oxo-9H-fluorene-1-carboxamides as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 9-oxo-9H-fluorene ring

被引：13

作者：

Kemnitzer, William ^{[1
]}

Sirisoma, Nilantha ^{[1
]}

Jiang, Songchun ^{[1
]}

Kasibhatla, Shailaja ^{[1
]}

Crogan-Grundy, Candace ^{[1
]}

Tseng, Ben ^{[1
]}

Drewe, John ^{[1
]}

Cai, Sui Xiong ^{[1
]}

机构：

[1] Epicept Corp, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

Apoptosis inducers; Anticancer agents; SAR; Tubulin inhibition; CHEMICAL GENETICS APPROACH; HTS ASSAY; ANTICANCER AGENTS; GAMBOGIC ACID; PART; 4-ARYL-4H-CHROMENES; RECEPTOR; TARGETS; DESIGN; DRUGS;

D O I：

10.1016/j.bmcl.2009.11.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As a continuation of our studies of apoptosis inducing 9-oxo-9H-fluorene-1-carboxamides as potential anticancer agents, we explored modi. cation of the 9-oxo-9H-fluorene ring. SAR studies showed that most changes to the 9-oxo-9H-fluorene ring were not well tolerated, except the 9H-fluorene (2b) and dibenzothiophene (2d) analogs, which were about twofold less active than the 9-oxo-9H-fluorene analog 2a. Significantly, introduction of substitutions at the 7-position of the 9-oxo-9H-fluorene ring led to compounds 5a-5c with improved activity. Compound 5a was found to have EC50 values of 0.15-0.29 mu M against T47D, HCT116, and SNU398 cells, about fivefold more potent than the original lead 2a. As opposed to the original lead compound 2a, compounds 5a-5b were active in a tubulin inhibition assay, indicating a change of mechanism of action. The potent azido analog 5c could be utilized for target identification. (C) 2009 Published by Elsevier Ltd.

引用

页码：1288 / 1292

页数：5

共 31 条

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