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Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor
Molecules ( IF 4.6 ) Pub Date : 2020-04-02 , DOI: 10.3390/molecules25071642
Ulviye Acar Çevik 1, 2 , Betül Kaya Çavuşoğlu 3 , Begüm Nurpelin Sağlık 1, 2 , Derya Osmaniye 1, 2 , Serkan Levent 1, 2 , Sinem Ilgın 4 , Yusuf Özkay 1, 2 , Zafer Asım Kaplancıklı 1
Affiliation  

In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC50 = 0.032 ± 0.042 µM, compared to IC50 = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a–5p) were calculated by QikProp 4.8 software.

中文翻译:

新型苯并咪唑-三唑噻二嗪衍生物作为芳香化酶抑制剂的合成、对接研究及生物活性

在雌激素生物合成的最后一步,芳香酶催化雄激素转化为雌激素。芳香化酶抑制是控制雌激素相关疾病和雌激素水平的重要途径。在这项研究中,合成并研究了 16 种苯并咪唑-三唑噻二嗪衍生物作为有效的芳香酶抑制剂。首先,测试了这些化合物对人乳腺癌细胞系 (MCF-7) 的抗癌特性。对 MCF-7 细胞系中最活跃的化合物 5c、5e、5k 和 5m 进行进一步的体外芳香酶抑制试验,以确定其活性背后的可能作用机制。与来曲唑的 IC50 = 0.024 ± 0.001 µM 相比,化合物 5e 的芳香酶抑制活性略低于来曲唑,IC50 = 0.032 ± 0.042 µM。此外,将化合物 5e 和参考药物来曲唑对接到人胎盘芳香酶中,以预测它们与该酶的可能结合模式。最后,通过 QikProp 4.8 软件计算合成化合物 (5a-5p) 的 ADME 参数(吸收、分布、代谢和排泄)。
更新日期:2020-04-02
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