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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.

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 MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry and Drug Discovery

Profile image of BARRIE KELLAM

BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry



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.