title: 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.
abstract: 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.
authors.affiliation: Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kemnitzer
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhao
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Jia
authors.forename: John
authors.initials: J
authors.lastname: Herich
authors.forename: Denis
authors.initials: D
authors.lastname: Labreque
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
authors.forename: Karen
authors.initials: K
authors.lastname: Meerovitch
authors.forename: David
authors.initials: D
authors.lastname: Bouffard
authors.forename: Rabindra
authors.initials: R
authors.lastname: Rej
authors.forename: Real
authors.initials: R
authors.lastname: Denis
authors.forename: Charles
authors.initials: C
authors.lastname: Blais
authors.forename: Serge
authors.initials: S
authors.lastname: Lamothe
authors.forename: Giorgio
authors.initials: G
authors.lastname: Attardo
authors.forename: Henriette
authors.initials: H
authors.lastname: Gourdeau
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D001704:Biopolymers; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
chemical_list: C494722:2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene; D000970:Antineoplastic Agents; D001578:Benzopyrans; D001704:Biopolymers; D004149:Dioxoles; D014404:Tubulin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases