title: Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers.
abstract: We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC(50) values of 0.008 and 0.004microM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization.
authors.affiliation: EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kemnitzer
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: Chris
authors.initials: C
authors.lastname: May
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: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C542868:4-anilino-N-methylthieno(3,2-d)pyrimidine; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011743:Pyrimidines; D020169:Caspases