Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery.

Abstract

Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.

• Authors: Erica L Stone, Francesca Citossi, Rajinder Singh, Balvinder Kaur, Margaret Gaskell, Peter B Farmer, Anne Monks, Curtis Hose, Malcolm F G Stevens, Chee-Onn Leong, Michael Stocks, Barrie Kellam, Maria Marlow, Tracey D Bradshaw
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 21 Pg. 6891-9 (Nov 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26474663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole
• 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole
• Antineoplastic Agents
• Benzothiazoles
• DNA Adducts
• H2AX protein, human
• Histones
• Hydrogels
• Prodrugs
• Stilbenes
• Thiazoles
• Cytochrome P-450 CYP1A1
• Resveratrol

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzothiazoles (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromatography, High Pressure Liquid
• Cytochrome P-450 CYP1A1 (genetics, metabolism)
• DNA Adducts (analysis, metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation (drug effects)
• Histones (metabolism)
• Humans
• Hydrogels (chemistry)
• Microscopy, Confocal
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Resveratrol
• Stilbenes (chemistry)
• Thiazoles (chemical synthesis, chemistry, pharmacology)