Probing structural requirements for human topoisomerase I inhibition by a novel N1-Biphenyl fluoroquinolone

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 topoiso...

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Veröffentlicht in:	European journal of medicinal chemistry Jg. 172; S. 109 - 130
Hauptverfasser:	Delgado, Justine L., Lentz, Sarah R.C., Kulkarni, Chaitanya A., Chheda, Pratik R., Held, Hailey A., Hiasa, Hiroshi, Kerns, Robert J.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.06.2019 Elsevier
Schlagworte:	Anti-cancer Biphenyl Compounds - chemical synthesis Biphenyl Compounds - chemistry Biphenyl Compounds - pharmacology Catalytic inhibitors Chemistry, Medicinal DNA Topoisomerases, Type I - metabolism Dose-Response Relationship, Drug Fluoroquinolones Fluoroquinolones - chemical synthesis Fluoroquinolones - chemistry Fluoroquinolones - pharmacology hTopoI inhibitor Humans Life Sciences & Biomedicine Molecular Structure Pharmacology & Pharmacy Science & Technology Structure-Activity Relationship Topoisomerase Topoisomerase I Inhibitors - chemical synthesis Topoisomerase I Inhibitors - chemistry Topoisomerase I Inhibitors - pharmacology Fluoroquinolones Topoisomerase hTopoI inhibitor Anti-cancer Catalytic inhibitors MECHANISM BIPHENYL ROLES MODE hTopol inhibitor DNA GYRASE DERIVATIVES
ISSN:	0223-5234, 1768-3254, 1768-3254
Online-Zugang:	Volltext
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Zusammenfassung:	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. [Display omitted] •Novel quinolones act as catalytic inhibitors of hTopoI.•C-7 amine required for hTopoI catalytic inhibition.•N-1 biphenyl functional group intercalates between DNA base pairs.•Mechanism of DNA intercalation by N-1 biphenyl fluoroquinolones contributes to hTopoI inhibition.•Novel hTopoI inhibitors that do not increase DNA breaks.
Bibliographie:	NIH RePORTER ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254 1768-3254
DOI:	10.1016/j.ejmech.2019.03.040