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	Sean E O'Brien, Helen L Browne, Tracey D Bradshaw, Andrew D Westwell, Malcolm F Stevens, Charles A Laughton
Journal	Organic & biomolecular chemistry (Org Biomol Chem) Vol. 1 Issue 3 Pg. 493-7 (Feb 07 2003) ISSN: 1477-0520 [Print] England
PMID	12926251 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents Benzothiazoles Cations DNA Adducts Hydrocarbons, Fluorinated Thiazoles Cytochrome P-450 CYP1A1 benzothiazole
Topics	Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology) Benzothiazoles Binding Sites Biotransformation Breast Neoplasms (metabolism) Cations (metabolism) Cell Death (drug effects, physiology) Cytochrome P-450 CYP1A1 (antagonists & inhibitors, metabolism) DNA Adducts (drug effects) Dose-Response Relationship, Drug Female Humans Hydrocarbons, Fluorinated (chemistry, metabolism, pharmacology) Models, Molecular Oxidation-Reduction Thiazoles (chemistry, pharmacokinetics, pharmacology) Tumor Cells, Cultured

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!