title: Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure-activity relationships of fused rings at the 7,8-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 fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI50 of 8 nM in T47D cells.
authors.affiliation: Epicept Corporation, 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: Jianghong
authors.initials: J
authors.lastname: Zhao
authors.forename: Candace
authors.initials: C
authors.lastname: Crogan-Grundy
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.forename: Serge
authors.initials: S
authors.lastname: Lamothe
authors.forename: Henriette
authors.initials: H
authors.lastname: Gourdeau
authors.forename: Réal
authors.initials: R
authors.lastname: Denis
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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C521968:2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4,7-dihydropyrano(2,3-e)indole; D000970:Antineoplastic Agents; D001578:Benzopyrans; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D020169:Caspases