Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity** |
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Authors: | Bader I. Huwaimel Myla Bhakta Dr. Chaitanya A. Kulkarni Alexander S. Milliken Feifei Wang Prof. Aimin Peng Prof. Paul S. Brookes Prof. Paul C. Trippier |
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Affiliation: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106 USA;2. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106 USA;3. Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642 USA;4. Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583 USA |
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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 and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC50 values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC50 of 2.93±0.07 μM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer. |
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Keywords: | Drug Discovery Diazoxide Mitochondrial Complex II Prostate Cancer Triple-negative Breast Cancer |
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