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Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity

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Summary

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.

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Acknowledgements

We would like to thank Margaret A. Mysz, Lia G. Coicou, Brenda L. Koniar, and Nicole A. Larson for expert assistance.

Funding

This work was supported in part by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK), the NIH’s National Center for Advancing Translational Sciences grant UL1TR002494 (to HH), and the National Cancer Institute’s Developmental Therapeutic Program. We also received support from the University of Minnesota’s Center for Translational Medicine and the Masonic Cancer Center (to RJS). TRT acknowledges support of the NIH Predoctoral Training Program in Pharmacological Sciences (GM067795), the American Foundation for Pharmaceutical Education Predoctoral Fellowship Program, and the American Chemical Society Division of Medicinal Chemistry Fellowship sponsored by Richard B. Silverman-2012 Predoctoral. CAK and JLD acknowledge support of training fellowships from the University of Iowa Center for Biocatalysis and Bioprocessing and of the NIH-sponsored Predoctoral Training Program in Biotechnology (GM008365). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences.

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Author notes

  1. Lisa M. Oppegard

    Present address: College of Undergraduate Health Sciences, Northwestern Health Sciences University, Bloomington, MN, 55431, USA

  2. Tyrell R. Towle

    Present address: MedPharm Holdings, Denver, CO, 80239, USA

  3. Daryl J. Murry

    Present address: Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA

  4. Lisa M. Oppegard and Justine L. Delgado contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN, 55455, USA

    Lisa M. Oppegard, Delaney E. Hart, Bridget P. Williams, Sarah R. C. Lentz & Hiroshi Hiasa

  2. Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave., S321 Pharmacy Building, Iowa City, IA, 52242, USA

    Justine L. Delgado, Chaitanya A. Kulkarni, Tyrell R. Towle & Robert J. Kerns

  3. Center for Translational Medicine, University of Minnesota Academic Health Center, 515 Delaware Street SE, Room 2-191, Minneapolis, MN, 55455, USA

    Beverly J. Norris, Craig M. Flory & Robert J. Schumacher

  4. The Division of Pharmaceutics and Translational Therapeutics, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave., S321 Pharmacy Building, Iowa City, IA, 52242, USA

    Daryl J. Murry

Authors
  1. Lisa M. Oppegard
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  2. Justine L. Delgado
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  7. Sarah R. C. Lentz
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  8. Beverly J. Norris
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  12. Robert J. Kerns
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  13. Hiroshi Hiasa
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Corresponding author

Correspondence to Hiroshi Hiasa.

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The authors declare no competing financial interest.

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This article does not contain any studies with human participants performed by any of the authors. The animal studies were approved by the University of Minnesota Institutional Animal Care and Use Committee.

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Oppegard, L.M., Delgado, J.L., Kulkarni, C.A. et al. Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity. Invest New Drugs 37, 378–383 (2019). https://doi.org/10.1007/s10637-018-0666-x

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  • DOI: https://doi.org/10.1007/s10637-018-0666-x

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