title: Antitumor benzothiazoles. 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo.
abstract: A new series of 2-(4-aminophenyl)benzothiazoles substituted in the phenyl ring and benzothiazole moiety has been synthesized by simple, high-yielding routes. The parent molecule 5a shows potent inhibitory activity in vitro in the nanomolar range against a panel of human breast cancer cell lines, but is inactive (IC50 > 30 microM) against other cell types: activity against the sensitive breast lines MCF-7 and MDA 468 is characterized by a biphasic dose-response relationship. Structure-activity relationships derived using these cell types has revealed that activity follows the heterocyclic sequence benzothiazole > benzoxazole >> benzimidazole and that 2-(4-aminophenyl)benzothiazoles bearing a 3'-methyl- 9a, 3'-bromo- 9c, 3'-iodo- 9f, and 3'-chloro-substituent 9i are especially potent and their activity extends to ovarian, lung, and renal cell lines. Four compounds have been evaluated in vivo against human mammary carcinoma models in nude mice. Compound 9a showed the most potent growth inhibition against the ER+ (MCF-7 and BO) and ER- (MT-1 and MT-3) tumors. Our efforts to identify a pharmacological mechanism of action for these intriguing compounds have not, as yet, been successful.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nottingham, U.K.
authors.forename: D F
authors.initials: DF
authors.lastname: Shi
authors.forename: T D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: S
authors.initials: S
authors.lastname: Wrigley
authors.forename: C J
authors.initials: CJ
authors.lastname: McCall
authors.forename: P
authors.initials: P
authors.lastname: Lelieveld
authors.forename: I
authors.initials: I
authors.lastname: Fichtner
authors.forename: M F
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D052160:Benzothiazoles; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000090023:Metallothionein 3; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D052160:Benzothiazoles; D001583:Benzoxazoles; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D013844:Thiazoles; C005465:benzothiazole