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

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

doi:10.1016/j.bmc.2015.09.052

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

Bioorg Med Chem. 2015 Nov 1;23(21):6891-9. doi: 10.1016/j.bmc.2015.09.052. Epub 2015 Oct 3.

Affiliations

¹ School of Pharmacy, University of Nottingham, NG7 2RD, UK.
² Biocentre, University of Leicester, LE1 7RH, UK.
³ National Cancer Institute, Frederick, MD 21702-1202, USA.
⁴ School of Pharmacy and Health Sciences, International Medical University, 57000 Kuala Lumpur, Malaysia.

PMID: 26474663
DOI: 10.1016/j.bmc.2015.09.052

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.

Keywords: 5F 203; Antitumour benzothiazoles; DNA adducts; DNA double strand breaks; GW 610; Low molecular weight gelators (LMWGs).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
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 / analysis*
DNA Adducts / metabolism
Drug Resistance, Neoplasm
Gene Expression Regulation / drug effects
Histones / metabolism
Humans
Hydrogels / chemistry*
Microscopy, Confocal
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology
Resveratrol
Stilbenes / chemistry
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology

Substances

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