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

Stone, Erica L.; Citossi, Francesca; Singh, Rajinder; Kaur, Balvinder; Gaskell, Margaret; Farmer, Peter B.; Monks, Anne; Hose, Curtis; Stevens, Malcolm F.G.; Leong, Chee-Onn; Stocks, Michael; Kellam, Barrie; Marlow, Maria; Bradshaw, Tracey D.

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 (R2 > 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.

Citation

Stone, E. L., Citossi, F., Singh, R., Kaur, B., Gaskell, M., Farmer, P. B., …Bradshaw, T. D. (2015). Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery. Bioorganic and Medicinal Chemistry, 23(21), 6891-6899. https://doi.org/10.1016/j.bmc.2015.09.052

• Journal Article Type: Article
• Acceptance Date: Sep 30, 2015
• Online Publication Date: Oct 3, 2015
• Publication Date: 2015-11
• Deposit Date: Mar 27, 2019
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 21
• Pages: 6891-6899
• DOI: https://doi.org/10.1016/j.bmc.2015.09.052
• Keywords: Antitumour benzothiazoles; GW 6105F 203DNA adducts; DNA double strand breaks; Low molecular weight gelators (LMWGs)
• Public URL: https://nottingham-repository.worktribe.com/output/1696135
• Additional Information: This article is maintained by: Elsevier; Article Title: Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery; Journal Title: Bioorganic & Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bmc.2015.09.052; Content Type: article; Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.