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.

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.

Citation

Khomenko, T. M., Zakharenko, A. L., Kornienko, T. E., Chepanova, A. A., Dyrkheeva, N. S., Artemova, A. O., …Lavrik, O. I. (in press). New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan. International Journal of Molecular Sciences, 24(11), Article 9155. https://doi.org/10.3390/ijms24119155

• 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