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

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

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-h...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 24; no. 11; p. 9155
Main Authors: 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
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 23-05-2023
MDPI
Subjects:
Cancer
Cancer therapies
Care and treatment
Chemotherapy
Conjugates
coumarin
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Drug therapy
Drugs
enzyme inhibition
Inhibitors
Ligands
monoterpene
Phosphodiesterase
Phosphodiesterase I
synergy
Topotecan
Toxicity
Tumors
monoterpene
synergy
enzyme inhibition
DNA repair
coumarin
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Summary: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 IC in low micromolar or nanomolar ranges. Geraniol derivative was the most potent inhibitor with IC 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.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24119155