Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity*.
Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity*.
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DOI：
10.1002/cmdc.202000729
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发表时间：
2021-04-08
期刊：
影响因子：
3.4
通讯作者：
Trippier PC
中科院分区：
文献类型：
--
作者：
Huwaimel BI;Bhakta M;Kulkarni CA;Milliken AS;Wang F;Peng A;Brookes PS;Trippier PC
线粒体呼吸复合物II（CII），也称为琥珀酸脱氢酶，在线粒体代谢中起关键作用。已知但效力低的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降糖二氮嗪。在此，我们首次研究了苯并噻二嗪衍生物抑制CII的构效关系及其对癌细胞的作用。复合物II的抑制作用比二氮嗪增加了15倍，尽管IC 50值为微摩尔。新型衍生物的细胞毒性评价鉴定出了比二氮嗪具有更大的抗肿瘤作用的化合物，其中最有效的化合物在三阴性乳腺癌细胞模型中的IC 50为2.93 ±0.07 μM，对非恶性细胞具有高选择性，是临床药物5-氟尿嘧啶效力的两倍以上。没有发现细胞毒性和CII抑制之间的相关性，表明该支架的作用机制尚未确定。本文所述的衍生物代表了用于三阴性乳腺癌的治疗发现的有价值的命中化合物。对临床药物二氮嗪衍生的苯并噻二嗪支架进行构效关系研究。许多在前列腺癌和三阴性乳腺癌（TNBC）的细胞模型中具有增强的抗肿瘤活性的卤代衍生物被纯化。特别是，苄胺侧链取代基与苯并噻二嗪环的7-溴官能化结合，产生了降低TNBC细胞活力的有希望的活性，其选择性是非恶性细胞的10倍。
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.
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影响因子：
6.1
作者：
Kong M;Ba M;Liang H;Shao P;Yu T;Wang Y
通讯作者：
Wang Y
影响因子：
16.1
作者：
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通讯作者：
Bari, Ferenc
DOI：
10.1016/j.jamcollsurg.2013.01.048
发表时间：
2013-06-01
影响因子：
5.2
作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
Busija, DW
影响因子：
4.8
作者：
Dong, Lan-Feng;Jameson, Victoria J. A.;Neuzil, Jiri
通讯作者：
Neuzil, Jiri