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New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan

Khomenko, Tatyana M.; Zakharenko, Alexandra L.; Kornienko, Tatyana E.; Chepanova, Arina A.; Dyrkheeva, Nadezhda S.; Artemova, Anastasia O.; Korchagina, Dina V.; Achara, Chigozie; Curtis, Anthony; Reynisson, Jóhannes; Volcho, Konstantin P.; Salakhutdinov, Nariman F.; Lavrik, Olga I.

Authors

Tatyana M. Khomenko

Alexandra L. Zakharenko

Tatyana E. Kornienko

Arina A. Chepanova

Nadezhda S. Dyrkheeva

Anastasia O. Artemova

Dina V. Korchagina

Chigozie Achara

Konstantin P. Volcho

Nariman F. Salakhutdinov

Olga I. Lavrik



Abstract

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.

Journal Article Type Article
Acceptance Date May 19, 2023
Online Publication Date May 23, 2023
Deposit Date Jun 7, 2023
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 24
Issue 11
Article Number 9155
DOI https://doi.org/10.3390/ijms24119155
Keywords Inorganic Chemistry; Organic Chemistry; Physical and Theoretical Chemistry; Computer Science Applications; Spectroscopy; Molecular Biology; General Medicine; Catalysis