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. 1. Structure-activity relationships of the carboxamide group

被引：20

作者：

Kemnitzer, William ^{[1
]}

Sirisoma, Nilantha ^{[1
]}

Nguyen, Bao ^{[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 Inc, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 11期

关键词：

Apoptosis inducers; HTS; Anticancer agents; SAR study; ANTICANCER AGENTS; GAMBOGIC ACID; CANCER; MECHANISM; DEATH;

D O I：

10.1016/j.bmcl.2009.04.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

N-(2-Methylphenyl)-9-oxo-9H-fluorene-1-carboxamide (2a) was identified as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 2a was found to be active with sub-micromolar potencies for both caspase induction and growth inhibition in T47D human breast cancer, HCT116 human colon cancer, and SNU398 hepatocellular carcinoma cancer cells. It arrested HCT116 cells in G(2)/M followed by apoptosis as assayed by the flow cytometry. Structure-activity relationship (SAR) studies of the carboxamide group identified the lead compound N-(2-(1H-pyrazol-1-yl)phenyl)-9-oxo-9H-fluorene-1-carboxamide (6s). Compound 6s, with increased aqueous solubility, was found to retain the broad activity in the caspase activation assay and in the cell growth inhibition assay with sub-micromolar EC50 and GI(50) values in T47D, HCT116, and SNU398 cells, respectively. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3045 / 3049

页数：5

共 24 条

[1] A fluorescence-based high-throughput assay for antimicrotubule drugs [J].