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Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Nov 01; Vol. 23 (21), pp. 6891-9. Date of Electronic Publication: 2015 Oct 03. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Benzothiazoles chemical synthesis
Benzothiazoles chemistry
Benzothiazoles pharmacology
Cell Line, Tumor
Cell Survival drug effects
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP1A1 genetics
Cytochrome P-450 CYP1A1 metabolism
DNA Adducts metabolism
Drug Resistance, Neoplasm
Gene Expression Regulation drug effects
Histones metabolism
Humans
Microscopy, Confocal
Prodrugs chemistry
Prodrugs pharmacology
Resveratrol
Stilbenes chemistry
Thiazoles chemical synthesis
Thiazoles pharmacology
Antineoplastic Agents chemical synthesis
DNA Adducts analysis
Hydrogels chemistry
Prodrugs chemical synthesis
Thiazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 23
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26474663
- Full Text :
- https://doi.org/10.1016/j.bmc.2015.09.052