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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/11/9155 |
| _version_ | 1797597480395735040 |
|---|---|
| author | Tatyana M. Khomenko Alexandra L. Zakharenko Tatyana E. Kornienko Arina A. Chepanova Nadezhda S. Dyrkheeva Anastasia O. Artemova Dina V. Korchagina Chigozie Achara Anthony Curtis Jóhannes Reynisson Konstantin P. Volcho Nariman F. Salakhutdinov Olga I. Lavrik |
| author_facet | Tatyana M. Khomenko Alexandra L. Zakharenko Tatyana E. Kornienko Arina A. Chepanova Nadezhda S. Dyrkheeva Anastasia O. Artemova Dina V. Korchagina Chigozie Achara Anthony Curtis Jóhannes Reynisson Konstantin P. Volcho Nariman F. Salakhutdinov Olga I. Lavrik |
| author_sort | Tatyana M. Khomenko |
| collection | DOAJ |
| description | 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<sub>50</sub> in low micromolar or nanomolar ranges. Geraniol derivative <b>33a</b> was the most potent inhibitor with IC<sub>50</sub> 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. |
| first_indexed | 2024-03-11T03:06:39Z |
| format | Article |
| id | doaj.art-743746e1c2074f6ba1e368147fdd7119 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:06:39Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-743746e1c2074f6ba1e368147fdd71192023-11-18T07:55:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411915510.3390/ijms24119155New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to TopotecanTatyana M. Khomenko0Alexandra L. Zakharenko1Tatyana E. Kornienko2Arina A. Chepanova3Nadezhda S. Dyrkheeva4Anastasia O. Artemova5Dina V. Korchagina6Chigozie Achara7Anthony Curtis8Jóhannes Reynisson9Konstantin P. Volcho10Nariman F. Salakhutdinov11Olga I. Lavrik12N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UKSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UKSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UKN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, RussiaTyrosyl-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<sub>50</sub> in low micromolar or nanomolar ranges. Geraniol derivative <b>33a</b> was the most potent inhibitor with IC<sub>50</sub> 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.https://www.mdpi.com/1422-0067/24/11/9155coumarinmonoterpeneenzyme inhibitionDNA repairsynergy |
| spellingShingle | Tatyana M. Khomenko Alexandra L. Zakharenko Tatyana E. Kornienko Arina A. Chepanova Nadezhda S. Dyrkheeva Anastasia O. Artemova Dina V. Korchagina Chigozie Achara Anthony Curtis Jóhannes Reynisson Konstantin P. Volcho Nariman F. Salakhutdinov Olga I. Lavrik New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan International Journal of Molecular Sciences coumarin monoterpene enzyme inhibition DNA repair synergy |
| title | New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan |
| title_full | New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan |
| title_fullStr | New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan |
| title_full_unstemmed | New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan |
| title_short | New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan |
| title_sort | new 5 hydroxycoumarin based tyrosyl dna phosphodiesterase i inhibitors sensitize tumor cell line to topotecan |
| topic | coumarin monoterpene enzyme inhibition DNA repair synergy |
| url | https://www.mdpi.com/1422-0067/24/11/9155 |
| work_keys_str_mv | AT tatyanamkhomenko new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT alexandralzakharenko new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT tatyanaekornienko new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT arinaachepanova new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT nadezhdasdyrkheeva new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT anastasiaoartemova new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT dinavkorchagina new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT chigozieachara new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT anthonycurtis new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT johannesreynisson new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT konstantinpvolcho new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT narimanfsalakhutdinov new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan AT olgailavrik new5hydroxycoumarinbasedtyrosyldnaphosphodiesteraseiinhibitorssensitizetumorcelllinetotopotecan |