Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

• Published in: ChemMedChem Vol. 16; no. 7; pp. 1143 - 1162
• Main Authors: Huwaimel, Bader I., Bhakta, Myla, Kulkarni, Chaitanya A., Milliken, Alexander S., Wang, Feifei, Peng, Aimin, Brookes, Paul S., Trippier, Paul C.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 08.04.2021; Wiley Subscription Services, Inc
• Subjects: 5-Fluorouracil; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Benzothiadiazines - chemical synthesis; Benzothiadiazines - chemistry; Benzothiadiazines - pharmacology; Breast cancer; Cancer; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemical compounds; Chemistry, Medicinal; Cytotoxicity; Diazoxide; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Halogenation; Humans; Life Sciences & Biomedicine; Metabolism; Mitochondrial Complex II; Molecular Structure; Pharmacology; Pharmacology & Pharmacy; Prostate Cancer; Science & Technology; Selectivity; Structure-Activity Relationship; Succinate dehydrogenase; Toxicity; Triple-negative Breast Cancer; Mitochondrial Complex II; Prostate Cancer; Diazoxide; Triple-negative Breast Cancer; Drug Discovery; MITOCHONDRIAL COMPLEX-II
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000729

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. Improving selectivity: Halogenated diazoxide derivatives with enhanced antineoplastic activity in cellular models of prostate cancer and triple‐negative breast cancer (TNBC) have been identified in SAR studies. In particular benzylamine side chain substituents combined with 7‐bromo functionalization to the benzothiadiazine ring results in promising activity to reduce cell viability of TNBC cells with tenfold selectivity over nonmalignant cells.