Document Detail

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.
MedLine Citation:
PMID:  15566300     Owner:  NLM     Status:  MEDLINE    
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.
William Kemnitzer; John Drewe; Songchun Jiang; Hong Zhang; Yan Wang; Jianghong Zhao; Shaojuan Jia; John Herich; Denis Labreque; Richard Storer; Karen Meerovitch; David Bouffard; Rabindra Rej; Real Denis; Charles Blais; Serge Lamothe; Giorgio Attardo; Henriette Gourdeau; Ben Tseng; Shailaja Kasibhatla; Sui Xiong Cai
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-29     Completed Date:  2005-01-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6299-310     Citation Subset:  IM    
Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
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MeSH Terms
Antineoplastic Agents / chemistry*,  pharmacology
Benzopyrans / chemistry*,  pharmacology
Caspases / metabolism*
Cell Line, Tumor
Cell Nucleus / drug effects
Cell Proliferation / drug effects
Dioxoles / chemistry*,  pharmacology
Drug Screening Assays, Antitumor
Enzyme Activation
Poly(ADP-ribose) Polymerases / metabolism
Structure-Activity Relationship
Tubulin / chemistry
Reg. No./Substance:
0/2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene; 0/Antineoplastic Agents; 0/Benzopyrans; 0/Biopolymers; 0/Dioxoles; 0/Tubulin; EC Polymerases; EC 3.4.22.-/Caspases

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