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新型苯并咪唑-三唑噻二嗪衍生物作为芳香酶抑制剂的合成、对接研究及生物活性。

Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey.

Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey.

出版信息

Molecules. 2020 Apr 2;25(7):1642. doi: 10.3390/molecules25071642.

Abstract

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 , , , and 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 showed slight less potent aromatase inhibitory activity than that of letrozole with IC = 0.032 ± 0.042 µM, compared to IC = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 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 (-) were calculated by QikProp 4.8 software.

摘要

在雌激素生物合成的最后一步中,芳香酶将雄激素催化转化为雌激素。芳香酶抑制是控制与雌激素相关疾病和雌激素水平的重要方法。在这项研究中,合成了十六种苯并咪唑-三唑噻二嗪衍生物,并将其作为有效的芳香酶抑制剂进行了研究。首先,这些化合物被测试了对人乳腺癌细胞系(MCF-7)的抗癌特性。对 MCF-7 细胞系最具活性的化合物、、、和进行了进一步的体外芳香酶抑制酶活性测定,以确定其活性的潜在作用机制。与来曲唑的 IC = 0.024 ± 0.001 µM 相比,化合物的芳香酶抑制活性略低于来曲唑,IC = 0.032 ± 0.042 µM。此外,化合物和参考药物来曲唑被对接到人胎盘芳香酶酶中,以预测它们与酶的可能结合模式。最后,通过 QikProp 4.8 软件计算了合成化合物(-)的 ADME 参数(吸收、分布、代谢和排泄)。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ea/7180718/1ddc17ec2246/molecules-25-01642-sch001.jpg

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