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Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

revised on 23.06.2020, 21:03 and posted on 25.06.2020, 11:42 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.


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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.