Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Arch Pharm (Weinheim). 2020 May;353(5):e2000008. doi: 10.1002/ardp.202000008. Epub 2020 Mar 11.
Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3-[4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenyl]-6-(substituted phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized. First, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF-7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b, 5c, 5e, and 5g on the MCF-7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole-triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors.
芳香酶参与雌激素的生物合成，因此是乳腺癌的关键靶点。在这项研究中，为了鉴定新的芳香酶酶抑制剂，合成了 7 种 3-[4-(5-甲基-1H-苯并[d]咪唑-2-基)苯基]-6-(取代苯基)-7H-[1,2,4]三唑并[3,4-b][1,3,4]噻二嗪衍生物。首先，进行了 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐 (MTT) 测定，以确定合成化合物对 MCF-7 细胞系的抑制活性。对具有活性的化合物 5b、5c、5e 和 5g 在 MCF-7 细胞系上进行了芳香酶抑制活性测定。化合物 5g 显示出显著的芳香酶抑制活性（IC = 0.037 ± 0.001 µM）。有趣的是，该化合物在苯环的 2 和 4 位带有二氟取代基，显示出最强的芳香酶抑制活性，而对正常健康细胞系 (NIH3T3) 没有明显的细胞毒性。此外，通过对接研究分析了最佳活性化合物与酶活性位点之间的相互作用。这项研究的结果表明，苯并咪唑-三唑噻二嗪衍生物是很有前途的化合物，应进一步开发作为新型芳香酶抑制剂。
