简介：人类拓扑异构酶1（TOP1）是多种抗癌化合物的重要靶点。针对TOP1的抑制剂的设计和发现对于抗癌药物的开发具有重要意义。吴茱萸碱和噻吩并[2,3-d]吡啶杂合物显示出潜在的抗肿瘤活性。在此，研究了这些杂种的抗胃癌活性。方法：采用甲基噻唑基四唑鎓法测定不同浓度的10种吴茱萸碱衍生物对胃癌细胞系SGC-7901的抑制作用。化合物EVO-1和EVO-6强烈抑制胃癌细胞增殖，抑制率分别为81.17%±5.08%和80.92%±2.75%。为了发现这两种衍生物的结构和活性之间的关系，利用密度泛函理论研究了它们的优化几何结构、自然布居电荷、前沿分子轨道和分子静电势。为了阐明其抗胃癌机制，针对 TOP1 进行了分子对接、分子动力学模拟和结合自由能计算。结果：结果表明，这些化合物可以嵌入到切割的DNA结合位点中，形成TOP1-DNA-配体三元复合物，并且配体在切割的DNA结合位点上保持安全，形成稳定的三元复合物。由于化合物 EVO-1 与 TOP1 的结合自由能 (-38.33 kcal·mol-1) 低于化合物 EVO-6 (-33.25 kcal·mol-1)，因此化合物 EVO-1 可能是一种更有效的抗肿瘤药物。 -比化合物EVO-6更好的胃癌剂。讨论：因此，化合物EVO-1可能是一种有前途的抗胃癌候选药物。这项研究可能有助于新型 TOP1 抑制剂的设计和开发。版权所有 © 2024 Liu、Xue、Bai、Yan、Long、Guo、Yan、Huang、Zhou 和 Tang。

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33 kcal·mol-1) was lower than that of compound EVO-6 (-33.25 kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.Copyright © 2024 Liu, Xue, Bai, Yan, Long, Guo, Yan, Huang, Zhou and Tang.