Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase

Tyrell R. Towle; Chaitanya A. Kulkarni; Lisa M. Oppegard; Bridget P. Williams; Taylor A. Picha; Hiroshi Hiasa; Robert J. Kerns

doi:10.1016/j.bmcl.2018.03.085

Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase

Tyrell R. Towle, Chaitanya A. Kulkarni, Lisa M. Oppegard, Bridget P. Williams, Taylor A. Picha, Hiroshi Hiasa, Robert J. Kerns

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

16 Scopus citations

Abstract

Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 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-1 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-1 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.

Original language	English (US)
Pages (from-to)	1903-1910
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2018.03.085
State	Published - Jun 1 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Research Grant R01 AI87671 to RJK. Tyrell Towle 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. Chaitanya Kulkarni acknowledges the support of a training fellowship from the University of Iowa Center for Biocatalysis and Bioprocessing and of the NIH-sponsored Predoctoral Training Program in Biotechnology (GM008365).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

Bacterial resistance
DNA gyrase
Fluoroquinolone
Topoisomerase

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10.1016/j.bmcl.2018.03.085

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938125

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Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives : Probing for binding contact with the active site tyrosine of gyrase. / Towle, Tyrell R.; Kulkarni, Chaitanya A.; Oppegard, Lisa M. et al.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 10, 01.06.2018, p. 1903-1910.

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

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abstract = "Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 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-1 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-1 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.",

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note = "Funding Information: This work was supported by National Institutes of Health (NIH) Research Grant R01 AI87671 to RJK. Tyrell Towle 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. Chaitanya Kulkarni acknowledges the support of a training fellowship from the University of Iowa Center for Biocatalysis and Bioprocessing and of the NIH-sponsored Predoctoral Training Program in Biotechnology (GM008365). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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AU - Hiasa, Hiroshi

AU - Kerns, Robert J.

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N2 - Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 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-1 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-1 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.

AB - Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 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-1 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-1 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.

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Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase

Abstract

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