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

Lisa M. Oppegard; Justine L. Delgado; Chaitanya A. Kulkarni; Tyrell R. Towle; Delaney E. Hart; Bridget P. Williams; Sarah R.C. Lentz; Beverly Norris; Craig M Flory; Robert J Schumacher; Daryl J. Murry; Robert J. Kerns; Hiroshi Hiasa

doi:10.1007/s10637-018-0666-x

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

Lisa M. Oppegard, Justine L. Delgado, Chaitanya A. Kulkarni, Tyrell R. Towle, Delaney E. Hart, Bridget P. Williams, Sarah R.C. Lentz, Beverly Norris, Craig M Flory, Robert J Schumacher, Daryl J. Murry, Robert J. Kerns, Hiroshi Hiasa

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	378-383
Number of pages	6
Journal	Investigational New Drugs
Volume	37
Issue number	2
DOIs	https://doi.org/10.1007/s10637-018-0666-x
State	Published - Apr 15 2019

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

Colon cancer
DNA intercalator
Fluoroquinolone
Topoisomerase I
Topoisomerase II

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10637-018-0666-x

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409185

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Oppegard, L. M., Delgado, J. L., Kulkarni, C. A., Towle, T. R., Hart, D. E., Williams, B. P., Lentz, S. R. C., Norris, B., Flory, C. M., Schumacher, R. J., Murry, D. J., Kerns, R. J., & Hiasa, H. (2019). Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity. Investigational New Drugs, 37(2), 378-383. https://doi.org/10.1007/s10637-018-0666-x

Oppegard, LM, Delgado, JL, Kulkarni, CA, Towle, TR, Hart, DE, Williams, BP, Lentz, SRC, Norris, B , Flory, CM , Schumacher, RJ, Murry, DJ, Kerns, RJ & Hiasa, H 2019, 'Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity', Investigational New Drugs, vol. 37, no. 2, pp. 378-383. https://doi.org/10.1007/s10637-018-0666-x

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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 {\textquoteleft}topoisomerase poisoning{\textquoteright}. 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{\textquoteright}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.",

keywords = "Colon cancer, DNA intercalator, Fluoroquinolone, Topoisomerase I, Topoisomerase II",

author = "Oppegard, {Lisa M.} and Delgado, {Justine L.} and Kulkarni, {Chaitanya A.} and Towle, {Tyrell R.} and Hart, {Delaney E.} and Williams, {Bridget P.} and Lentz, {Sarah R.C.} and Beverly Norris and Flory, {Craig M} and Schumacher, {Robert J} and Murry, {Daryl J.} and Kerns, {Robert J.} and Hiroshi Hiasa",

note = "Funding Information: Funding This work was supported in part by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK), the NIH{\textquoteright}s National Center for Advancing Translational Sciences grant UL1TR002494 (to HH), and the National Cancer Institute{\textquoteright}s Developmental Therapeutic Program. We also received support from the University of Minnesota{\textquoteright}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. Publisher Copyright: {\textcopyright} 2018, Springer Science+Business Media, LLC, part of Springer Nature.",

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AU - Oppegard, Lisa M.

AU - Delgado, Justine L.

AU - Kulkarni, Chaitanya A.

AU - Towle, Tyrell R.

AU - Hart, Delaney E.

AU - Williams, Bridget P.

AU - Lentz, Sarah R.C.

AU - Norris, Beverly

AU - Flory, Craig M

AU - Schumacher, Robert J

AU - Murry, Daryl J.

AU - Kerns, Robert J.

AU - Hiasa, Hiroshi

N1 - Funding Information: 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. Publisher Copyright: © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

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N2 - 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.

AB - 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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KW - DNA intercalator

KW - Fluoroquinolone

KW - Topoisomerase I

KW - Topoisomerase II

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

Abstract

Bibliographical note

Keywords

UN SDGs

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