Journal article
Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity
Investigational new drugs, Vol.37(2), pp.378-383
04/2019
DOI: 10.1007/s10637-018-0666-x
PMCID: PMC6409185
PMID: 30198058
Abstract
Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i.e., without poisoning it. Surprisingly, these compounds are more effective in inhibiting the catalytic activities of human and bacterial topoisomerase I. The National Cancer Institute's 60 human tumor cell lines screen revealed significant anti-proliferative activities with 217 and 227 against the majority of 60 cancer cell lines. A proof of concept in vivo efficacy study using an HT-29 xenograft model of human colorectal cancer showed that 217 could inhibit the proliferation of human colorectal cancer cells to a degree comparable to fluorouracil in mice. Although 227 also exhibited anti-proliferative activity, it was not as effective as 217 in this xenograft model. These novel fluoroquinolones may serve as promising lead compounds for the development of new anticancer drugs.
Details
- Title: Subtitle
- Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity
- Creators
- Lisa M Oppegard - University of MinnesotaJustine L Delgado - University of IowaChaitanya A Kulkarni - University of IowaTyrell R Towle - University of IowaDelaney E Hart - University of MinnesotaBridget P Williams - University of MinnesotaSarah R C Lentz - University of MinnesotaBeverly J Norris - University of MinnesotaCraig M Flory - University of MinnesotaRobert J Schumacher - University of MinnesotaDaryl J Murry - University of Nebraska Medical CenterRobert J Kerns - University of IowaHiroshi Hiasa - University of Minnesota
- Resource Type
- Journal article
- Publication Details
- Investigational new drugs, Vol.37(2), pp.378-383
- DOI
- 10.1007/s10637-018-0666-x
- PMID
- 30198058
- PMCID
- PMC6409185
- ISSN
- 0167-6997
- eISSN
- 1573-0646
- Grant note
- T32 GM067795 / NIGMS NIH HHS T32 GM008365 / National Institute of General Medical Sciences R01 AI087671 / NIAID NIH HHS UL1 TR002494 / National Center for Advancing Translational Sciences R01 AI087671 / National Institute of Allergy and Infectious Diseases Extramural Activities UL1 TR002494 / NCATS NIH HHS T32 GM008365 / NIGMS NIH HHS T32 GM067795 / National Institute of General Medical Sciences
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Holden Comprehensive Cancer Center; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365888602771
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