Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor
Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor
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DOI：
10.3390/molecules25071642
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发表时间：
2020-04-01
期刊：
影响因子：
4.6
通讯作者：
Kaplancikli, Zafer Asim
中科院分区：
文献类型：
--
作者：
Cevik, Ulviye Acar;Cavusoglu, Betuel Kaya;Kaplancikli, Zafer Asim
在雌激素生物合成的最后一步，芳香化酶催化雄激素转化为雌激素。抑制芳香化酶是控制雌激素相关疾病和雌激素水平的重要途径。本研究合成了16个苯并咪唑-三唑并噻二嗪衍生物，并对其作为芳香酶抑制剂进行了研究。首先，测试这些化合物对人乳腺癌细胞系（MCF-7）的抗癌特性。对MCF-7细胞系上最具活性的化合物5c、5e、5 k和5 m进行进一步的体外芳香酶抑制测定，以确定其活性背后的可能作用机制。化合物5e显示出比来曲唑略弱的芳香酶抑制活性，其IC 50 = 0.032 +/- 0.042 μ M，而来曲唑的IC 50 = 0.024 +/- 0.001 μ M。此外，化合物5e和参比药物来曲唑对接到人胎盘芳香化酶，以预测它们与酶的可能结合模式。最后，通过QikProp 4.8软件计算合成化合物（5a-5 p）的ADME参数（吸收、分布、代谢和排泄）。
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 mu M, compared to IC50 = 0.024 +/- 0.001 mu M 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.