Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

22 May 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

Diaxoxide
Mitochondrial Subunit II
Prostate Cancer
Triple Negative Breast Cancer

Supplementary materials

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Benzothiadiazine SI FINAL
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