Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3-b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors

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• 作者：Peng-Hui Li ; Ping Zeng ; Shuo-Bin Chen ; Pei-Fen Yao ; Yan-Wen Mai ; Jia-Heng Tan ; Tian-Miao Ou ; Shi-Liang Huang ; Ding Li ; Lian-Quan Gu ; Zhi-Shu Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：238-252
• 全文大小：717K
• ISSN：1520-4804

文摘

Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of 1,3-benzoazolyl-substituted pyrrolo[2,3-b]pyrazine derivatives were designed, synthesized, and evaluated as potential Topo II catalytic inhibitors. It was found that some of derivatives had good antiproliferative activity on seven cancer cell lines, especially on HL-60/MX2, a cancer cell line derivative from HL-60 that is resistant to Topo II poison. Topo II mediated DNA relaxation assay results showed that derivatives could significantly inhibit the activity of Topo II, and the structure–activity relationship studies indicated the importance of the alkylamino side chain and the benzoazolyl group. Further mechanism studies revealed that derivatives function as Topo II nonintercalative catalytic inhibitors and may block the ATP binding site of Topo II. Moreover, flow cytometric analysis showed that this class of compounds could induce apoptosis of HL-60 cells.