National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar (Mohali), Punjab-160062, India.
J Med Chem. 2011 Jul 28;54(14):5013-30. doi: 10.1021/jm200235u. Epub 2011 Jun 23.
On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.
基于已知拓扑异构酶 II 催化抑制剂的结构和初步分子对接研究，双环 N-融合氨基咪唑被预测为潜在的拓扑异构酶 II 抑制剂。它们通过多组分反应合成，并在体外解连环、松弛、切割复合物和 DNA 插入实验中针对人拓扑异构酶 IIα（hTopoIIα）进行评估。在所研究的 8 种不同双环支架的 31 种化合物中，发现具有合适取代基的咪唑并吡啶、咪唑并吡唑和咪唑并吡嗪对 hTopoIIα的催化活性具有很强的抑制作用，而不显示 DNA 插入。分子对接研究和分子动力学（MD）模拟分析、ATPase 动力学和 ATP 依赖性质粒松弛实验表明，标题化合物通过阻断 ATP 结合位点可能具有催化抑制作用。N-融合氨基咪唑在肾癌细胞系和乳腺癌细胞系中表现出很强的抗癌活性，对正常细胞的毒性低，与依托泊苷和氟尿嘧啶相比在肾癌细胞系中具有较高的活性，并且对细胞迁移具有很强的抑制作用。这些化合物被发现能在 G1/S 期发挥凋亡作用。
