Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity*.

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 complex II 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 non-malignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, 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. Structure-activity relationship studies are conducted on the benzothiadiazine scaffold originating from the clincial agent Diazoxide. A number of halogenated derivatives with enhanced antineoplastic activity in cellular models of prostate cancer and triple negative breast cancer (TNBC) are idenified. 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 10-fold selectivity over non-malignant cells.

线粒体呼吸链复合物II（CII），也称为琥珀酸脱氢酶，在线粒体代谢中起着关键作用。已知的但效力较低的CII抑制剂对癌细胞具有选择性细胞毒性，包括基于苯并噻二嗪的抗低血糖药物二氮嗪。在此，我们首次研究了苯并噻二嗪衍生物对CII抑制的构效关系及其对癌细胞的影响。与二氮嗪相比，对复合物II的抑制作用提高了15倍，尽管其半数抑制浓度（IC₅₀）值为微摩尔级别。对新型衍生物的细胞毒性评估发现，有些化合物的抗肿瘤作用比二氮嗪强得多，其中最有效的化合物在三阴性乳腺癌细胞模型中的IC₅₀为2.93 ± 0.07 μM，对非恶性细胞具有高选择性，效力是临床药物5 - 氟尿嘧啶的两倍多。未发现细胞毒性与CII抑制之间存在相关性，这表明该化合物骨架的作用机制尚未明确。本文所述的衍生物是三阴性乳腺癌治疗发现中有价值的先导化合物。 对源自临床药物二氮嗪的苯并噻二嗪骨架进行了构效关系研究。 鉴定出了一些在前列腺癌和三阴性乳腺癌（TNBC）细胞模型中具有增强抗肿瘤活性的卤代衍生物。特别是苄胺侧链取代基与苯并噻二嗪环上的7 - 溴官能团化相结合，对降低TNBC细胞的活力具有良好活性，对非恶性细胞的选择性为10倍。