339062-83-8Relevant academic research and scientific papers
Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure-activity relationships of the 4-aryl group
Kemnitzer, William,Drewe, John,Jiang, Songchun,Zhang, Hong,Wang, Yan,Zhao, Jianghong,Jia, Shaojuan,Herich, John,Labreque, Denis,Storer, Richard,Meerovitch, Karen,Bouffard, David,Rej, Rabindra,Denis, Real,Blais, Charles,Lamothe, Serge,Attardo, Giorgio,Gourdeau, Henriette,Tseng, Ben,Kasibhatla, Shailaja,Cai, Sui Xiong
, p. 6299 - 6310 (2004)
By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7- (dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G2/M stage and to induce apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). Through structure-activity relationship (SAR) studies of the 4-aryl group, a 4- and 7-fold increase in potency was obtained from the screening hit 1a to the lead compounds 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-(dimethylamino) -4H-chromene (1c) and 2-amino-3-cyano-7-(dimethylamino)-4-(5-methyl-3-pyridyl)- 4H-chromene (4e), with an EC50 of 19 and 11 nM in the caspase activation assay in T47D breast cancer cells, respectively. The 2-amino-4-aryl-3-cyano-7-(dimethylamino)-4H-chromenes also were found to be highly active in the growth inhibition MTT assay, with GI50 values in the low nanomolar range for compound 1c. Significantly, compound 1c was found to have a GI50 value of 2 nM in the paclitaxel resistant, p-glycoprotein overexpressed, MESSA/DX5 tumor cells. Functionally, compound 1c was found to be a potent inhibitor of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. These results confirm that the cell-based caspase activation assay is a powerful tool for the discovery of potent apoptosis inducers and suggest that the 4-aryl-4H-chromenes have the potential to be developed into future anticancer agents.
SUBSTITUTED 4H-CHROMENE AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
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Page 40, (2008/06/13)
The present invention is directed to substituted 4H-chromene and analogs thereof, represented by the general Formula I: wherein A, B, X, Y, Z and R5 are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
