Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity
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...
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| Published in: | Investigational new drugs Vol. 37; no. 2; pp. 378 - 383 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Springer US
01.04.2019
Springer Nature B.V |
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| ISSN: | 0167-6997, 1573-0646, 1573-0646 |
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| Abstract | 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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| AbstractList | 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.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. 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. SummaryFluoroquinolone-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. 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. |
| Author | Norris, Beverly J. Towle, Tyrell R. Murry, Daryl J. Williams, Bridget P. Schumacher, Robert J. Flory, Craig M. Hart, Delaney E. Delgado, Justine L. Lentz, Sarah R. C. Oppegard, Lisa M. Hiasa, Hiroshi Kerns, Robert J. Kulkarni, Chaitanya A. |
| AuthorAffiliation | 1 Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455, U.S.A 3 Center for Translational Medicine, University of Minnesota Academic Health Center, 515 Delaware Street SE, Room 2-191, Minneapolis, Minnesota 55455, U.S.A 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, Iowa 52242, U.S.A 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, Iowa 52242, U.S.A |
| AuthorAffiliation_xml | – name: 3 Center for Translational Medicine, University of Minnesota Academic Health Center, 515 Delaware Street SE, Room 2-191, Minneapolis, Minnesota 55455, U.S.A – name: 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, Iowa 52242, U.S.A – name: 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, Iowa 52242, U.S.A – name: 1 Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455, U.S.A |
| Author_xml | – sequence: 1 givenname: Lisa M. surname: Oppegard fullname: Oppegard, Lisa M. organization: Department of Pharmacology, University of Minnesota Medical School, College of Undergraduate Health Sciences, Northwestern Health Sciences University – sequence: 2 givenname: Justine L. surname: Delgado fullname: Delgado, Justine L. organization: Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa – sequence: 3 givenname: Chaitanya A. surname: Kulkarni fullname: Kulkarni, Chaitanya A. organization: Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa – sequence: 4 givenname: Tyrell R. surname: Towle fullname: Towle, Tyrell R. organization: Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, MedPharm Holdings – sequence: 5 givenname: Delaney E. surname: Hart fullname: Hart, Delaney E. organization: Department of Pharmacology, University of Minnesota Medical School – sequence: 6 givenname: Bridget P. surname: Williams fullname: Williams, Bridget P. organization: Department of Pharmacology, University of Minnesota Medical School – sequence: 7 givenname: Sarah R. C. surname: Lentz fullname: Lentz, Sarah R. C. organization: Department of Pharmacology, University of Minnesota Medical School – sequence: 8 givenname: Beverly J. surname: Norris fullname: Norris, Beverly J. organization: Center for Translational Medicine, University of Minnesota Academic Health Center – sequence: 9 givenname: Craig M. surname: Flory fullname: Flory, Craig M. organization: Center for Translational Medicine, University of Minnesota Academic Health Center – sequence: 10 givenname: Robert J. surname: Schumacher fullname: Schumacher, Robert J. organization: Center for Translational Medicine, University of Minnesota Academic Health Center – sequence: 11 givenname: Daryl J. surname: Murry fullname: Murry, Daryl J. organization: The Division of Pharmaceutics and Translational Therapeutics, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center – sequence: 12 givenname: Robert J. surname: Kerns fullname: Kerns, Robert J. organization: Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa – sequence: 13 givenname: Hiroshi orcidid: 0000-0002-8165-2232 surname: Hiasa fullname: Hiasa, Hiroshi email: hiasa001@umn.edu organization: Department of Pharmacology, University of Minnesota Medical School |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30198058$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1007_s00044_021_02749_y crossref_primary_10_1016_j_biomaterials_2023_122093 crossref_primary_10_1080_13543776_2025_2558899 crossref_primary_10_1016_j_ejmech_2019_03_040 crossref_primary_10_3390_ph16101456 crossref_primary_10_1080_17460441_2023_2246366 |
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| DOI | 10.1007/s10637-018-0666-x |
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| Keywords | Topoisomerase I Fluoroquinolone Colon cancer DNA intercalator Topoisomerase II |
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Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that... Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target... SummaryFluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target... |
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| SubjectTerms | 5-Fluorouracil Animals Antibiotics Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic drugs Antiproliferatives Antitumor agents Apoptosis Aromatic compounds Biotechnology Cancer Catalysis Catalytic activity Cell Proliferation Colonic Neoplasms - drug therapy Colonic Neoplasms - enzymology Colonic Neoplasms - pathology Colorectal cancer Colorectal carcinoma Coordination compounds Deoxyribonucleic acid DNA DNA topoisomerase DNA topoisomerase (ATP-hydrolysing) DNA topoisomerase IV DNA Topoisomerases, Type I - chemistry Drug development Female Fluoroquinolones Fluoroquinolones - chemistry Fluoroquinolones - pharmacology Humans In vivo methods and tests Lead compounds Medicine Medicine & Public Health Mice Mice, Nude Mode of action Oncology Pharmacology/Toxicology Poisoning Short Report Studies Topoisomerase I Inhibitors - chemistry Topoisomerase I Inhibitors - pharmacology Tumor cell lines Tumor Cells, Cultured Xenograft Model Antitumor Assays Xenografts Xenotransplantation |
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| Title | Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity |
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