title: 2-Aryl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols as a class of antitumor agents selectively active in securin(-/-) cells.
abstract: A series of 2-(4-aminophenyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols have been developed as antitumor agents that showed high selectivity against aneuploid cell lines (vs diploid cell lines). Structure-activity relationship studies showed that a hydroxymethyl group at the 2-position of the phenyl ring increased potency and selectivity. A pyrrolidinyl group at the 4-position of the phenyl ring was comparable to a dimethylamino group. The corresponding 5-aza analogs, 2-(4-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridin-7-ols, retained potency and high level of selectivity against aneuploid cell growth (vs diploid cells). These 5-aza compounds exhibited higher water solubility and higher metabolic stability than the corresponding carba analogs. Compound 19 showed the highest potency against MCF-7 and MDA-MB-361 lines and was selected for further evaluation.
authors.affiliation: Discovery Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. zhangn@wyeth.com
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Chuansheng
authors.initials: C
authors.lastname: Niu
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.forename: Erik
authors.initials: E
authors.lastname: Upeslacis
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Shoba
authors.initials: S
authors.lastname: Ragunathan
authors.forename: Edward
authors.initials: E
authors.lastname: Rosfjord
mesh_terms: D000782:Aneuploidy; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D064249:Securin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human