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
| Autor: | Richard Storer, Ben Tseng, Denis Labreque, John Drewe, Giorgio Attardo, Shailaja Kasibhatla, Jianghong Zhao, Henriette Gourdeau, Yan Wang, Songchun Jiang, David Y. Bouffard, Rabindra Rej, Real Denis, Hong Zhang, William Kemnitzer, Serge Lamothe, Sui Xiong Cai, Karen Meerovitch, John Herich, Charles Blais, Shaojuan Jia |
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| Rok vydání: | 2004 |
| Předmět: |
Antineoplastic Agents
Apoptosis Dioxoles Jurkat cells Flow cytometry chemistry.chemical_compound Structure-Activity Relationship Biopolymers Tubulin Cell Line Tumor Drug Discovery medicine Humans MTT assay Benzopyrans Fragmentation (cell biology) Cytotoxicity Caspase Cell Proliferation Cell Nucleus biology medicine.diagnostic_test Chemistry Enzyme Activation Biochemistry Caspases biology.protein Molecular Medicine Growth inhibition Drug Screening Assays Antitumor Poly(ADP-ribose) Polymerases |
| Zdroj: | Journal of medicinal chemistry. 47(25) |
| ISSN: | 0022-2623 |
| Popis: | 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 G(2)/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 EC(50) 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 GI(50) values in the low nanomolar range for compound 1c. Significantly, compound 1c was found to have a GI(50) value of 2 nM in the paclitaxel resistant, p-glycoprotein overexpressed, MES-SA/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. |
| Databáze: | OpenAIRE |
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