title: Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7-phenyl-(E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay.
abstract: We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7-(4-methylphenyl)-(E)-2,3,6,7-tetrahydro-1,4-thiazepine (2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-(E)-2,3,6,7-tetrahydro-1,4-thiazepine (5d) was identified as a potent apoptosis inducer with an EC(50) value of 0.08 microM in T47D cells, which was >15-fold more potent than screening hit 2a. Compound 5d also was found to be highly active in a growth inhibition assay with a GI(50) value of 0.05 microM in T47D cells and to function as an inhibitor of tubulin polymerization.
authors.affiliation: EpiCept Corporation, San Diego, CA 92121, USA.
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: Emma
authors.initials: E
authors.lastname: Shelton
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Robert M
authors.initials: RM
authors.lastname: Yee
authors.forename: Joane
authors.initials: J
authors.lastname: Litvak
authors.forename: Martin
authors.initials: M
authors.lastname: Sendzik
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Spencer
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry* / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D013841:Thiazepines; D014404:Tubulin; D020169:Caspases