Journal article
Activity of Quinolone CP-115,955 Against Bacterial and Human Type II Topoisomerases Is Mediated by Different Interactions
Biochemistry (Easton), Vol.54(5), pp.1278-1286
02/10/2015
DOI: 10.1021/bi501073v
PMCID: PMC4427193
PMID: 25586498
Abstract
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 IIa 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-metal 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-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIa 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.
Details
- Title: Subtitle
- Activity of Quinolone CP-115,955 Against Bacterial and Human Type II Topoisomerases Is Mediated by Different Interactions
- Creators
- Katie J. Aldred - Vanderbilt UniversityHeidi A. Schwanz - University of IowaGangqin Li - University of IowaBenjamin H. Williamson - University of IowaSylvia A. McPherson - University of Alabama at BirminghamCharles L. Turnbough - University of Alabama at BirminghamRobert J. Kerns - University of IowaNeil Osheroff - VA Tennessee Valley Healthcare System
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.54(5), pp.1278-1286
- Publisher
- Amer Chemical Soc
- DOI
- 10.1021/bi501073v
- PMID
- 25586498
- PMCID
- PMC4427193
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Number of pages
- 9
- Grant note
- American Foundation for Pharmaceutical Education AI81775; AI87671; GM033944 / National Institutes of Health Research Grants; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32CA009582 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01GM033944 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) I01 Bx002198 / United States Veterans Administration Merit Review award T32 CA09582; T32 GM008365 / National Institutes of Health Grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01BX002198 / Veterans Affairs; US Department of Veterans Affairs R01AI087671 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 02/10/2015
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365876702771
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