The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds

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• 作者：Brian B. Hasinoff ; Hong Liang ; Xing Wu ; Lynn J. Guziec ; Frank S. Guziec Jr. ; Kyle Marshall ; Jack C. Yalowich
• 关键词：Bisanthrapyrazole ; Bisintercalating ; Anticancer ; DNA-binding ; Topoisomerase II ; DNA ; Molecular modeling ; Docking ; Cytotoxicity ; K562 cells ; Cardiotoxic
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：1 April 2008
• 年：2008
• 卷：16
• 期：7
• 页码：3959-3968
• 全文大小：510 K

文摘

Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of ester-coupled bisanthrapyrazole derivatives of 7-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]anthra[1,9-cd]pyrazol-6(2H)-one (AP9) were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should not be cardiotoxic like the anthracyclines. Based on the docking scores of a series of bisanthrapyrazoles with different numbers of methylene linkers (n) that were docked into an X-ray structure of double-stranded DNA, five bisanthrapyrazoles (n = 1–5) were selected for synthesis and physical and biological evaluation. The synthesized compounds were evaluated for DNA binding and bisintercalation by measuring the DNA melting temperature increase, for growth inhibitory effects on the human erythroleukemic K562 cell line, and for DNA topoisomerase II-mediated cleavage of DNA and inhibition of DNA topoisomerase II decatenation activities. The results suggest that the bisanthrapyrazoles with n = 2–5 formed bisintercalation complexes with DNA. In conclusion, a novel group of bisintercalating anthrapyrazole compounds have been designed, synthesized and biologically evaluated as possible anticancer agents.