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.
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.
Kemnitzer
William
W
Epicept Corporation, Inc, San Diego, CA 92121, USA.
Sirisoma
Nilantha
N
Nguyen
Bao
B
Jiang
Songchun
S
Kasibhatla
Shailaja
S
Crogan-Grundy
Candace
C
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005449:Fluorenes; C541976:N-(2-(1H-pyrazol-1-yl)phenyl)-9-oxo-9H-fluorene-1-carboxamide; D011720:Pyrazoles; D020169:Caspases