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 hTopoI inhibition. Characterization of each analog for inhibition of hTopoI 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 hTopoI 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 hTopoI.
Original language | English (US) |
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Pages (from-to) | 109-130 |
Number of pages | 22 |
Journal | European Journal of Medicinal Chemistry |
Volume | 172 |
DOIs | |
State | Published - Jun 15 2019 |
Bibliographical note
Funding Information:We would like to thank Nicholas R. Vance for expert assistance and guidance. This work was supported in part by the National Institutes of Health (NIH) grants R01 AI087671 (to RJK) and HL127479 (to HH). We also received a Drug Discovery Pilot Program Award from the Department of Pharmacology (to HH). JLD, CAK, and PRC acknowledge support of training fellowships from the University of Iowa Center for Biocatalysis and Bioprocessing and of the NIH-sponsored Predoctoral Training Program in Biotechnology ( GM008365 ).
Publisher Copyright:
© 2019 Elsevier Masson SAS
Keywords
- Anti-cancer
- Catalytic inhibitors
- Fluoroquinolones
- Topoisomerase
- hTopoI inhibitor