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Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

preprint
revised on 23.06.2020 and posted on 25.06.2020 by Bader Huwaimel, Myla Bhakta, Chaitanya A. Kulkarni, Alexander S. Milliken, Feifei Wang, Aimin Peng, Paul Brookes, Paul C. Trippier

Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition for the first time. A number of more potent derivatives were identified. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with greater anticancer effect than the parent; two benzothiadiazine derivative classes (24a-d and 30a, 30c, 30d) that possess activity to reduce the cell viability of 22Rv1 prostate cancer cells and five novel 7-fluorobenzothiadiazine derivatives which possessed significant cytotoxicity in a cellular model of triple negative breast cancer. No correlation between cytotoxicity and CII inhibition was found, indicating an as yet undefined mechanism of action of this scaffold.

Funding

AKR1C3 Inhibitors as Chemotherapeutic Potentiators

National Cancer Institute

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SIRT1, Acidosis & Metabolism in Cardioprotection

National Heart Lung and Blood Institute

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North Texas Clinical Pharmacology Cancer Core

Cancer Prevention and Research Institute of Texas

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University of Nebraska Medical Center

Fred and Pamela Buffett Cancer Center

History

Email Address of Submitting Author

paul.trippier@unmc.edu

Institution

University of Nebraska Medical Center

Country

USA

ORCID For Submitting Author

0000-0002-4947-5782

Declaration of Conflict of Interest

A provisional patent (US 63/027180, ‘Halogenated Benzothiazines for the Treatment of Cancer’) describing the compounds in this manuscript has been filed.

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