Journal article
Design, synthesis, and evaluation of novel N-l fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase
Bioorganic & medicinal chemistry letters, Vol.28(10), pp.1903-1910
06/01/2018
DOI: 10.1016/j.bmcl.2018.03.085
PMCID: PMC5938125
PMID: 29661533
Abstract
Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-l position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-l position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-l position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-l position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II. (C) 2018 Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Design, synthesis, and evaluation of novel N-l fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase
- Creators
- Tyrell R. Towle - University of IowaChaitanya A. Kulkarni - University of IowaLisa M. Oppegard - University of MinnesotaBridget P. Williams - University of MinnesotaTaylor A. Picha - 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
- Bioorganic & medicinal chemistry letters, Vol.28(10), pp.1903-1910
- Publisher
- Elsevier
- DOI
- 10.1016/j.bmcl.2018.03.085
- PMID
- 29661533
- PMCID
- PMC5938125
- ISSN
- 0960-894X
- eISSN
- 1464-3405
- Number of pages
- 8
- Grant note
- American Chemical Society Division of Medicinal Chemistry Fellowship University of Iowa Center for Biocatalysis and Bio-processing P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) American Foundation for Pharmaceutical Education Predoctoral Fellowship Program T32GM067795 / 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) R01 AI87671 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA GM008365 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA GM067795 / NIH Predoctoral Training Program in Pharmacological Sciences R01AI087671 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 06/01/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366031502771
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