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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 11; pp. 3045 - 3049
• Main Authors: Kemnitzer, William, Sirisoma, Nilantha, Nguyen, Bao, Jiang, Songchun, Kasibhatla, Shailaja, Crogan-Grundy, Candace, Tseng, Ben, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2009; Elsevier
• Subjects: Anticancer agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis inducers; Biological and medical sciences; Caspases - metabolism; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Fluorenes - chemical synthesis; Fluorenes - chemistry; Fluorenes - pharmacology; General aspects; HCT116 Cells; HTS; Humans; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; SAR study; Structure-Activity Relationship; Anticancer agents; Apoptosis inducers; SAR study; HTS; Antineoplastic agent; High throughput screening; Solid tumor; Cysteine endopeptidases; Liver; Cytotoxicity; Structure activity relation; Pyrazole derivatives; Aromatic compound; Colon; Mammary gland; Tumor cell; Human; Enzyme; Caspase; Tricyclic compound; Ketone; In vitro; Peptidases; Cell line; Hydrolases; Carboxamide; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.009

The synthesis and SAR of a group of apoptosis-inducing 9-oxo-9H-fluorene-1-carboxamides with modifications at the carboxamide group are reported. 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 G2/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 GI50 values in T47D, HCT116, and SNU398 cells, respectively.