Activity of Quinolone CP-115,955 Against Bacterial and Human Type II Topoisomerases Is Mediated by Different Interactions

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• 作者：Katie J. Aldred ; Heidi A. Schwanz ; Gangqin Li ; Benjamin H. Williamson ; Sylvia A. McPherson ; Charles L. Turnbough ; Jr. ; Robert J. Kerns ; Neil Osheroff
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：February 10, 2015
• 年：2015
• 卷：54
• 期：5
• 页码：1278-1286
• 全文大小：451K
• ISSN：1520-4995

文摘

CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase II伪 was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. On the basis of the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water鈥搈etal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water鈥搈etal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase II伪 in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential.