N-Fused Imidazoles As Novel Anticancer Agents That Inhibit Catalytic Activity of Topoisomerase II伪 and Induce Apoptosis in G1/S Phase

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• 作者：Ashish T. Baviskar ; Chetna Madaan ; Ranjan Preet ; Purusottam Mohapatra ; Vaibhav Jain ; Amit Agarwal ; Sankar K. Guchhait ; Chanakya N. Kundu ; Uttam C. Banerjee ; Prasad V. Bharatam
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5013-5030
• 全文大小：1479K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

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 inihibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase II伪 (hTopoII伪) 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 hTopoII伪 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.