Discovery of 4-aryl-2-oxo-2H-chromenes as a new series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 20; pp. 5571 - 5575
• Main Authors: KEMNITZER, William, SONGCHUN JIANG, TSENG, Ben, DREWE, John, SUI XIONG CAI, HONG ZHANG, KASIBHATLA, Shailaja, CROGAN-GRUNDY, Candace, BLAIS, Charles, ATTARDO, Giorgio, DENIS, Real, LAMOTHE, Serge, GOURDEAU, Henriette
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.10.2008
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Pharmaceutical - methods; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; Drug Design; Drug Screening Assays, Antitumor; Enzyme Activation; General aspects; Humans; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Pyrroles - chemistry; Structure-Activity Relationship; Antineoplastic agent; High throughput screening; Solid tumor; Nitrile; Cysteine endopeptidases; Liver; Cytotoxicity; Oxygen heterocycle; Structure activity relation; Bicyclic compound; Bromine Organic compounds; Aromatic compound; Colon; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Ether; Enzyme; Benzene derivatives; Caspase; Lactone; Anticancer agents; Tricyclic compound; In vitro; Peptidases; Cell line; Hydrolases; Apoptosis inducers; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.09.011

As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as potential anticancer agents, we explored the removal of the chiral center at the 4-position and prepared a series of 4-aryl-2-oxo-2H-chromenes. It was found that, in general, removal of the chiral center and replacement of the 2-amino group with a 2-oxo group were tolerated and 4-aryl-2-oxo-2H-chromenes exhibited SAR similar to 4-aryl-2-amino-4H-chromenes. The 4-aryl-2-oxo-2H-chromenes with a N-methyl pyrrole fused at the 7,8-positions were highly active with compound 2a having an EC(50) value of 13 nM in T47D cells. It was found that an OMe group was preferred at the 7-position. 7-NMe(2), 7-NH(2), 7-Cl and 7,8 fused pyrido analogs all had low potency. These 4-aryl-2-oxo-2H-chromenes are a series of potent apoptosis inducers with potential advantage over the 4-aryl-2-amino-4H-chromenes series via elimination of the chiral center at the 4-position.