Journal article
Probing structural requirements for human topoisomerase I inhibition by a novel N1-Biphenyl fluoroquinolone
European journal of medicinal chemistry, Vol.172, pp.109-130
06/15/2019
DOI: 10.1016/j.ejmech.2019.03.040
PMCID: PMC6499389
PMID: 30959322
Abstract
Fluoroquinolones substituted with N-1 biphenyl and napthyl groups were discovered to act as catalytically inhibitors of human topoisomerases I and II, and to possess anti-proliferative activity in vivo. Structural requirements for these novel quinolones to inhibit catalytic activity of human topoisomerase I have not been explored. In this work novel derivatives of the N-1 biphenyl fluoroquinolone were designed, synthesized and evaluated to understand structural requirements of the C-3 carboxylic acid, C-6 fluorine, C-7 aminomethylpyrrolidine, C-8 methoxy, and the N-1 biphenyl functional groups for hTopol inhibition. Characterization of each analog for inhibition of hTopol catalytic inhibition reveals critical insight into structural requirements of these novel quinolones for activity. Additionally, results of DNA binding and modeling studies suggest that N-1 biphenyl fluoroquinolones intercalate between the DNA base pairs with the N-1 biphenyl functional group, rather than the quinolone core, and that this mode of DNA intercalation contributes to inhibition of hTopol by these novel structures. The results presented here support further development and evaluation of N-1 biphenyl fluoroquinolone analogs as a novel class of anti-cancer agents that act through catalytic inhibition of hTopol. (C) 2019 Elsevier Masson SAS. All rights reserved.
Details
- Title: Subtitle
- Probing structural requirements for human topoisomerase I inhibition by a novel N1-Biphenyl fluoroquinolone
- Creators
- Justine L. Delgado - University of IowaSarah R. C. Lentz - University of MinnesotaChaitanya A. Kulkarni - University of IowaPratik R. Chheda - University of IowaHailey A. Held - University of MinnesotaHiroshi Hiasa - University of MinnesotaRobert J. Kerns - Univ Iowa, Coll Pharm, Dept Pharmaceut Sci & Expt Therapeut, Div Med & Nat Prod Chem, 115 S Grand Ave,S321 Pharm Bldg, Iowa City, IA 52242 USA
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.172, pp.109-130
- DOI
- 10.1016/j.ejmech.2019.03.040
- PMID
- 30959322
- PMCID
- PMC6499389
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier
- Number of pages
- 22
- Grant note
- P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U01HL127479 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) University of Iowa Center for Biocatalysis and Bioprocessing GM008365 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 AI087671; HL127479 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Department of Pharmacology T32GM008365 / 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)
- Language
- English
- Date published
- 06/15/2019
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366036202771
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