Molecular Diversity ( IF 3.9 ) Pub Date : 2020-08-23 , DOI: 10.1007/s11030-020-10131-0 Abdallah Turky 1 , Ashraf H Bayoumi 1 , Farag F Sherbiny 1, 2 , Khaled El-Adl 3, 4 , Hamada S Abulkhair 1, 5
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Abstract
The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC50 = 3.61 µM), followed by 21 which displayed IC50 value of 3.93 µM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand–protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles.
Graphic abstract
中文翻译：
通过抑制 STAT3 揭示 1,2,4-三唑-N-芳基酰胺杂化物的抗癌效力：合成和计算机机械研究。
摘要
在过去十年中，有效的 STAT3 抑制剂的发现获得了显着的推动。与这一趋势一致，考虑到 1,2,4-三唑已证实的生物学重要性，我们在此报告了新型 C3-连接的 1,2,4-三唑的设计、合成、药代动力学特征和体外抗癌活性- N-芳基酰胺杂化物及其在计算机上通过抑制 STAT3 提出的作用机制。1,2,4-三唑支架被选为特权环系统，嵌入在临床使用或仍在临床试验的各种抗癌药物的核心结构中。设计的 1,2,4-三唑衍生物是通过将三唑-硫酮部分通过酰胺亲水接头与不同的亲脂性片段连接起来合成的。进行了计算机模拟研究，以预测新杂交体对不同种类的人类癌细胞系以及非肿瘤细胞的细胞毒性。发现耐多药人乳腺癌细胞 (MDA-MB-231) 对合成化合物的细胞毒性作用最敏感，因此被选择用于评估体外抗癌活性。12显示出最高的效力（IC 50 = 3.61 µM），其次是21，显示出 3.93 µM 的IC 50值。此外，化合物14和23显示出与参考细胞毒剂多柔比星等效的活性。为了加强这些观察，获得的体外细胞毒性数据已在配体-蛋白质相互作用方面得到验证，并分析了新化合物的 ADMET 特性，以评估其作为良好候选药物的潜力。这项研究使我们确定了两种新型 C3 连接的 1,2,4-三唑-N-芳基酰胺杂化物，它们具有有趣的抗增殖潜力，可能是 STAT3 的先导抑制剂，具有良好的药代动力学特征。
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