title: Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 7- and 5-, 6-, 8-positions.
abstract: As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency. Di-substitution at the 7,8-positions, in general, was found to result in potent compounds. 7-NMe2, 7-NHEt, 7-OMe, and 7,8-di-NH2 analogs were found to have similar SAR for the 4-aryl group, and several 7-substituted and 7,8-di-substituted analogs were found to have similar potencies as the lead compound MX58151 (2a) both as caspase activators and inhibitors of cell proliferation.
authors.affiliation: Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kemnitzer
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhao
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Jia
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.forename: Candace
authors.initials: C
authors.lastname: Crogan-Grundy
authors.forename: Réal
authors.initials: R
authors.lastname: Denis
authors.forename: Nancy
authors.initials: N
authors.lastname: Barriault
authors.forename: Louis
authors.initials: L
authors.lastname: Vaillancourt
authors.forename: Sylvie
authors.initials: S
authors.lastname: Charron
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dodd
authors.forename: Giorgio
authors.initials: G
authors.lastname: Attardo
authors.forename: Denis
authors.initials: D
authors.lastname: Labrecque
authors.forename: Serge
authors.initials: S
authors.lastname: Lamothe
authors.forename: Henriette
authors.initials: H
authors.lastname: Gourdeau
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D020169:Caspases