title: Antitumor benzothiazoles. Frontier molecular orbital analysis predicts bioactivation of 2-(4-aminophenyl)benzothiazoles to reactive intermediates by cytochrome P4501A1.
abstract: The antitumor and metabolic activities of 2-(4-aminophenyl)benzothiazoles and their fluorinated analogues cannot be explained or predicted by conventional chemical means. Their mode of anti-cancer action involves metabolism of the benzothiazoles to an as yet unidentified reactive species. This species then forms DNA adducts which provoke cell death. The electronic structures and possible intermediates of these compounds have been computed quantum mechanically. The counter-intuitive patterns of metabolism can only be explained by considering the active intermediate to be a nitrenium ion. The distribution of the highest occupied molecular orbital for the nitrenium species derived from each fluorinated analogue correlates perfectly with the production, or otherwise, of an exportable metabolite. Further related compounds have been analyzed by this method and the predictions of their metabolism have subsequently been verified experimentally.
authors.affiliation: Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham, UK NG7 2RD.
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Helen L
authors.initials: HL
authors.lastname: Browne
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
authors.forename: Malcolm F
authors.initials: MF
authors.lastname: Stevens
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D052160:Benzothiazoles; D001665:Binding Sites; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002412:Cations; D018736:DNA Adducts; D006845:Hydrocarbons, Fluorinated; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1; C005465:benzothiazole