The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1H-thieno [2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A Docking simulation was performed to fit compound 6g and gifitinib into the EGFR to determine the probable binding models, and the binding sites and modes conformation of 6g and gifitinib were exactly similar, the two compounds were stabilized by hydrogen bond interactions with MET769. Combining with the biological activity evaluation, compound 6g demonstrated the most potent inhibitory activity (IC50 = 9.68 ± 1.95 μmol·L–1 for A549). Conclusively, 4,5-dihydro-1H-thieno[2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the EGFR tyrosine kinase inhibitors were discovered, and could be used as potential lead compounds against cancer cells.

中文翻译：

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发现 4,5-Dihydro-1H-thieno[2',3':2,3]thiepino [4,5-c]pyrazole-3-carboxamide 衍生物作为酪氨酸激酶抑制剂的潜在表皮生长因子受体

表皮生长因子受体 (EGFR) 的过度表达（称为上调）或过度活跃与多种癌症相关，已成为治疗选择性癌症的有吸引力的分子靶标。我们在此报告了一系列新型 4,5-dihydro-1H-thieno [2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide 衍生物的设计和合成以及筛选使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑 (MTT) 对 EGFR 高表达人 A549 细胞系的抑制活性。进行对接模拟以将化合物6g和吉非替尼拟合到EGFR中以确定可能的结合模型，并且6g和吉非替尼的结合位点和模式构象完全相似，两种化合物通过与MET769的氢键相互作用而稳定。结合生物活性评估，化合物6g显示出最有效的抑制活性（A549的IC50 = 9.68 ± 1.95 μmol·L–1）。最后，发现了 4,5-二氢-1H-噻吩并[2',3':2,3]噻吩并[4,5-c]吡唑-3-甲酰胺衍生物作为EGFR酪氨酸激酶抑制剂，并可用作对抗癌细胞的潜在先导化合物。