title: 2-(4-aminophenyl) benzothiazole: a potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines.
abstract: 2-(4-aminophenyl) benzothiazole (CJM -126) (Table 1 (1) and its analogues represent a potent and highly selective class of antitumor agents. These compounds in nanomolar range elicit potent growth inhibition in human-derived breast, colon, ovarian and renal tumour cell lines. Metabolism of benzothiazole plays a central role in its mode of action. Cytocrome P450 isoform, CYP1A1, biotransforms benzothiazoles, to active, as well as inactive metabolites. In vitro studies had confirmed that N-oxidation and N-acetylation (only 3' halogen congener) as main active metabolic transformation (generating cytotoxic electrophilic species), while C-6 oxidation and N-acetylation (except 3' halogen congener) as inactive metabolic transformation pathway. Generation of an inactive metabolite 2-(4-aminophenyl)-6-hydoxybenzothiazole [6-OH 126, (Table 1) (10)] is blocked by fluorinated analogue, substituted around benzothiazole nucleus, especially at 5-position. National Cancer Institute (NCI), USA, confirms this series as a unique mechanistic class distinct from clinically used chemotherapeutic agents. Benzothiazoles are potent aryl hydrocarbon receptor (AhR) agonists, binding to AhR results in induction of CYP1A1, causes generation of electrophilic reactive species which forms DNA adduct, ultimately resulting in cell death by activation of apoptotic machinery. To overcome the poor physiochemical and pharmaceutical properties (bioavailability problem) of this compounds, prodrug of benzothiazole derivatives were synthesized, which are introduced in clinical trails.
authors.affiliation: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport bypass Road, Gandhi Nagar, Bhopal (M.P) 462036, India.
authors.forename: Raghvendra
authors.initials: R
authors.lastname: Dubey
authors.forename: Prabhat K
authors.initials: PK
authors.lastname: Shrivastava
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Basniwal
authors.forename: Snehendu
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Narayana S Hari Narayana
authors.initials: NS
authors.lastname: Moorthy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C111133:2-(4-aminophenyl)benzothiazole; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1