期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 10, 页码 1903-1910出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.03.085
关键词
Bacterial resistance; Fluoroquinolone; DNA gyrase; Topoisomerase
资金
- National Institutes of Health (NIH) [R01 AI87671]
- NIH Predoctoral Training Program in Pharmacological Sciences [GM067795]
- American Foundation for Pharmaceutical Education Predoctoral Fellowship Program
- American Chemical Society Division of Medicinal Chemistry Fellowship
- University of Iowa Center for Biocatalysis and Bio-processing
- NIH [GM008365]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据