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

作者：Kemnitzer William; Sirisoma Nilantha; Nguyen Bao; Jiang Songchun; Kasibhatla Shailaja; Crogan Grundy Candace; Tseng Ben; Drewe John; Cai Sui Xiong^*

来源：Bioorganic & Medicinal Chemistry Letters, 2009, 19(11): 3045-3049.

DOI：10.1016/j.bmcl.2009.04.009

• Apoptosis inducers
• HTS
• Anticancer agents
• SAR study

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 EC(50) and GI(50) values in T47D, HCT116, and SNU398 cells, respectively.

• 出版日期2009-6-1