Department of Chemistry, Faculty of Sciences, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia; Laboratoire de Chimie & Electrochimie des Complexes Métalliques (LCECM) USTO-MB, Department of Chemistry, Faculty of Sciences, University of Sciences and Technology Mohamed Boudiaf, B.p. 1505 El M nouar, Oran 31000, Algeria.
Department of Chemistry, Faculty of Sciences, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.
Bioorg Chem. 2020 Jan;94:103446. doi: 10.1016/j.bioorg.2019.103446. Epub 2019 Nov 23.
This study reports an efficient and convenient regioselective synthesis of a novel series of S- and S,N-bis(acyclonucleoside) analogues carrying 5-(2-chlorophenyl)-2,4-dihydro-1,2,4-triazole-3-thione. A facile and straightforward synthesis of thiazolotriazole and triazolothiazines has also been reported. Structures of all newly synthesized compounds were well characterized by infrared IR, H and C nuclear magnetic resonance (NMR) and mass (MS) spectra analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using staurosporine as a reference drug against three different types: human liver cancer cell line (Hep G2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the S-acyclonucleoside analogues and S,N-bis(acyclonucleoside) analogues showed excellent activity with micromolar (µM) half maximal inhibitory concentration (IC) values against tumor cells. EGFR assay and tubulin inhibition assay analysis were performed for the most active compounds to get more details about their mechanism of action. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. Extensive structure activity relationship (SAR) analyses were also carried out.
本研究报道了一种高效、便捷的新型 S-和 S,N-双（杂环核苷）类似物的区域选择性合成方法，该类似物带有 5-(2-氯苯基)-2,4-二氢-1,2,4-三唑-3-硫酮。还报道了噻唑并三唑和三唑并噻嗪的简便合成方法。所有新合成化合物的结构均通过红外（IR）、氢（H）和碳（C）核磁共振（NMR）和质谱（MS）谱分析进行了很好的表征。根据（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）四唑（MTT）测定法，用依托泊苷作为参考药物，对三种不同类型的细胞（人肝癌细胞系（Hep G2）、密歇根癌症基金会-7（MCF-7）和人结直肠癌细胞系（HCT116））进行细胞毒性筛选。这些数据表明，这些新合成的化合物具有相当的抗癌活性。大多数 S-杂环核苷类似物和 S,N-双（杂环核苷）类似物的生物学数据显示出对肿瘤细胞具有优异的活性，其半数最大抑制浓度（IC）值为微摩尔（µM）。对最活跃的化合物进行了 EGFR 测定和微管蛋白抑制测定分析，以获取更多关于其作用机制的详细信息。为了评估和解释它们的结合亲和力，对 EGFR 和微管蛋白结合位点进行了分子对接模拟研究。将从分子对接研究中获得的结果与从细胞毒性筛选中获得的结果相关联。还进行了广泛的构效关系（SAR）分析。
