{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T10:21:48Z","timestamp":1769941308471,"version":"3.49.0"},"reference-count":61,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-14-00105"],"award-info":[{"award-number":["21-14-00105"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (\u2212)-usnic acid. Both (+)- and (\u2212)-enantiomers of compounds act equally effectively against Tdp1 with IC50 values in the range of 0.02\u20130.2 \u03bcM; only (\u2212)-enantiomers inhibited Tdp2 with IC50 values in the range of 6\u20139 \u03bcM. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide (CC50 3.0\u20133.9 \u03bcM in the presence of compounds and 2.4 \u03bcM the presence of DMSO) but potentiate it against Tdp2 knockout cells (CC50 1.2\u20131.6 \u03bcM in the presence of compounds against 2.3 \u03bcM in the presence of DMSO). We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with the effective inhibition of Tdp1, which could take over the functions of Tdp2.<\/jats:p>","DOI":"10.3390\/genes14101931","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T07:28:44Z","timestamp":1697095724000},"page":"1931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents"],"prefix":"10.3390","volume":"14","author":[{"given":"Alexandra L.","family":"Zakharenko","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8360-1041","authenticated-orcid":false,"given":"Nadezhda S.","family":"Dyrkheeva","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8627-3453","authenticated-orcid":false,"given":"Olga A.","family":"Luzina","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2798-2844","authenticated-orcid":false,"given":"Aleksandr S.","family":"Filimonov","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-9499","authenticated-orcid":false,"given":"Evgenii S.","family":"Mozhaitsev","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1916-1333","authenticated-orcid":false,"given":"Anastasia A.","family":"Malakhova","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1520-5549","authenticated-orcid":false,"given":"Sergey P.","family":"Medvedev","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suren M.","family":"Zakian","sequence":"additional","affiliation":[{"name":"Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nariman F.","family":"Salakhutdinov","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5980-8889","authenticated-orcid":false,"given":"Olga I.","family":"Lavrik","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2217\/fon.14.60","article-title":"Targeting DNA repair pathways for cancer treatment: What\u2019s new?","volume":"10","author":"Kelley","year":"2014","journal-title":"Future Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1111\/bph.12244","article-title":"Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer","volume":"169","author":"Curtin","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15387","DOI":"10.1073\/pnas.242259599","article-title":"The mechanism of topoisomerase I poisoning by a camptothecin analog","volume":"99","author":"Staker","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nrc2607","article-title":"Targeting DNA topoisomerase II in cancer chemotherapy","volume":"9","author":"Nitiss","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1021\/cb300648v","article-title":"Drugging topoisomerases: Lessons and challenges","volume":"8","author":"Pommier","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.dnarep.2014.03.020","article-title":"Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)","volume":"19","author":"Pommier","year":"2014","journal-title":"DNA Repair"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12009","DOI":"10.1073\/pnas.211429198","article-title":"The Tyrosyl-DNA Phosphodiesterase Tdp1 Is a Member of the Phospholipase D Superfamily","volume":"98","author":"Interthal","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/emboj.2009.9","article-title":"Tdp1 protects against oxidative DNA damage in non-dividing fission yeast","volume":"28","author":"Arcangioli","year":"2009","journal-title":"EMBO J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Povirk, L.F. (2012). Processing of damaged DNA ends for double-strand break repair in mammalian cells. ISRN Mol. Biol., 2012.","DOI":"10.5402\/2012\/345805"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"494","DOI":"10.3109\/03602532.2014.971957","article-title":"Tyrosyl-DNA Phosphodiesterase I Resolves Both Naturally and Chemically Induced DNA Adducts and Its Potential as a Therapeutic Target","volume":"46","author":"Comeaux","year":"2014","journal-title":"Drug Metab. Rev."},{"key":"ref_11","first-page":"1153","article-title":"Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts","volume":"2","author":"Brettrager","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4732","DOI":"10.1038\/sj.emboj.7601885","article-title":"Spinocerebellar ataxia with axonal neuropathy: Consequence of a Tdp1 recessive neomorphic mutation?","volume":"26","author":"Hirano","year":"2007","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.jmb.2007.07.055","article-title":"Mutation of a conserved active site residue converts tyrosyl-DNA phosphodiesterase I into a DNA topoisomerase I-dependent poison","volume":"372","author":"He","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1038\/sj.emboj.7600694","article-title":"SCAN1 mutant Tdp1 accumulates the enzyme\u2013DNA intermediate and causes camptothecin hypersensitivity","volume":"24","author":"Interthal","year":"2005","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4720","DOI":"10.1038\/sj.emboj.7601869","article-title":"TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo","volume":"26","author":"Katyal","year":"2007","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.dnarep.2009.02.002","article-title":"Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin","volume":"8","author":"Katyal","year":"2009","journal-title":"DNA Repair"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"55618","DOI":"10.1074\/jbc.M405042200","article-title":"TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II","volume":"279","author":"Barthelmes","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00280-003-0717-6","article-title":"Engineered resistance to camptothecin and antifolates by retroviral coexpression of tyrosyl DNA phosphodiesterase-I and thymidylate synthase","volume":"53","author":"Nivens","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.2174\/092986712802002590","article-title":"DNA repair and resistance to topoisomerase I inhibitors: Mechanisms, biomarkers and therapeutic targets","volume":"19","author":"Alagoz","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bcp.2011.09.021","article-title":"Role of tyrosyl-DNA phosphodiesterase 1 and inter-players in regulation of tumor cell sensitivity to topoisomerase I inhibition","volume":"83","author":"Perego","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"258","DOI":"10.4172\/1948-5956.1000280","article-title":"TDP1\/TOP1 ratio as a promising indicator for the response of small cell lung cancer to topotecan","volume":"6","author":"Meisenberg","year":"2014","journal-title":"J. Cancer Sci. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zakharenko, A.L., Luzina, O.A., Chepanova, A.A., Dyrkheeva, N.S., Salakhutdinov, N.F., and Lavrik, O.I. (2023). Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065781"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1074\/jbc.M110.181016","article-title":"TDP2\/TTRAP is the major 5\u2032-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage","volume":"286","author":"Zeng","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature08444","article-title":"A human 5\u2032-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage","volume":"461","author":"Ledesma","year":"2009","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.chembiol.2010.04.012","article-title":"DNA topoisomerases and their poisoning by anticancer and antibacterial drugs","volume":"17","author":"Pommier","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Herreros, F., Romero-Granados, R., Zeng, Z., Alvarez-Quil\u00f3n, A., Quintero, C., Ju, L., Umans, L., Vermeire, L., Huylebroeck, D., and Caldecott, K.W. (2013). TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003226"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/med.21587","article-title":"Dual DNA topoisomerase 1 and tyrosyl-DNA phosphodiesterase 1 inhibition for improved anticancer activity","volume":"39","author":"Zakharenko","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/nar\/gkx1219","article-title":"Tyrosyl-DNA phosphodiesterases: Rescuing the genome from the risks of relaxation","volume":"46","author":"Kawale","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12848","DOI":"10.1074\/jbc.M111.333963","article-title":"Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells","volume":"287","author":"Murai","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8371","DOI":"10.1093\/nar\/gks622","article-title":"TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1","volume":"40","author":"Zeng","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1158\/1535-7163.MCT-13-0551","article-title":"Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel","volume":"13","author":"Maede","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.ejmech.2018.10.055","article-title":"Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topotecan on in vivo tumor models","volume":"161","author":"Zakharenko","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Khomenko, T.M., Zakharenko, A.L., Chepanova, A.A., Ilina, E.S., Zakharova, O.D., Kaledin, V.I., Nikolin, V.P., Popova, N.A., Korchagina, D.V., and Reynisson, J. (2019). Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010126"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s10585-021-10113-y","article-title":"The influence of an enamine usnic acid derivative (a tyrosyl-DNA phosphodiesterase 1 inhibitor) on the therapeutic effect of topotecan against transplanted tumors in vivo","volume":"38","author":"Nikolin","year":"2021","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Chernyshova, I.A., Zakharenko, A.L., Kurochkin, N.N., Dyrkheeva, N.S., Kornienko, T.E., Popova, N.A., Nikolin, V.P., Ilina, E.S., Zharkov, T.D., and Kupryushkin, M.S. (2022). Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo. Molecules, 28.","DOI":"10.3390\/molecules28010323"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1021\/acschembio.5b01047","article-title":"Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2","volume":"11","author":"Marchand","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4669","DOI":"10.1021\/acs.jmedchem.9b00274","article-title":"Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide","volume":"9","author":"Kankanala","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.ejmech.2018.04.024","article-title":"Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2)","volume":"10","author":"Yu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.dnarep.2016.04.009","article-title":"Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing","volume":"43","author":"Kont","year":"2016","journal-title":"DNA Repair"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Dyrkheeva, N.S., Filimonov, A.S., Luzina, O.A., Orlova, K.A., Chernyshova, I.A., Kornienko, T.E., Malakhova, A.A., Medvedev, S.P., Zakharenko, A.L., and Ilina, E.S. (2021). New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111336"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Salomatina, O.V., Dyrkheeva, N.S., Popadyuk, I.I., Zakharenko, A.L., Ilina, E.S., Komarova, N.I., Reynisson, J., Salakhutdinov, N.F., Lavrik, O.I., and Volcho, K.P. (2021). New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2. Molecules, 27.","DOI":"10.3390\/molecules27010072"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1134\/S1068162016020084","article-title":"Biological activity of usnic acid and its derivatives: Part 1. Activity against unicellular organisms","volume":"42","author":"Luzina","year":"2016","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1134\/S1068162016030109","article-title":"Biological activity of usnic acid and its derivatives: Part 2. effects on higher organisms. Molecular and physicochemical aspects","volume":"42","author":"Luzina","year":"2016","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Filimonov, A.S., Chepanova, A.A., Luzina, O.A., Zakharenko, A.L., Zakharova, O.D., Ilina, E.S., Dyrkheeva, N.S., Kuprushkin, M.S., Kolotaev, A.V., and Khachatryan, D.S. (2019). New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors. Molecules, 24.","DOI":"10.3390\/molecules24203711"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"Immunol. Methods"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/nsmb.2418","article-title":"Mechanism of repair of 5\u2032-topoisomerase II\u2013DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2","volume":"19","author":"Schellenberg","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","article-title":"OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules","volume":"15","author":"Roos","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_50","unstructured":"Polovinka, M.P., Salakhutdinov, N.F., and Panchenko, M.Y. (2008). Method for Preparing Usninic Acid. (Patent RU2317076)."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s10600-012-0258-5","article-title":"Synthesis of aurones based on usninic acid","volume":"48","author":"Luzina","year":"2012","journal-title":"Chem. Nat. Compd."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00018-019-03367-z","article-title":"Molecular mechanisms of topoisomerase 2 DNA-protein crosslink resolution","volume":"77","author":"Riccio","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1093\/nar\/gkw228","article-title":"Reversal of DNA damage induced Topoisomerase 2 DNA\u2013protein crosslinks by Tdp2","volume":"44","author":"Schellenberg","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1021\/acs.jnatprod.6b00979","article-title":"Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin","volume":"79","author":"Zakharenko","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1055\/a-0681-7069","article-title":"Inhibitory Effect of New Semisynthetic Usnic Acid Derivatives on Human Tyrosyl-DNA Phosphodiesterase 1","volume":"85","author":"Dyrkheeva","year":"2019","journal-title":"Planta Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s11101-019-09605-3","article-title":"Enantioselective activity of usnic acid: A comprehensive review and future perspectives","volume":"18","author":"Galanty","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s11101-020-09717-1","article-title":"Usnic acid: From an ancient lichen derivative to promising biological and nanotechnology applications","volume":"20","author":"Macedo","year":"2021","journal-title":"Phytochem. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3275","DOI":"10.1021\/acs.jmedchem.6b01565","article-title":"Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2)","volume":"60","author":"Wang","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.bmc.2016.02.015","article-title":"Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons","volume":"24","author":"Beck","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ivankin, D.I., Dyrkheeva, N.S., Zakharenko, A.L., Ilina, E.S., Zarkov, T.O., Reynisson, J., Luzina, O.A., Volcho, K.P., Salakhutdinov, N.F., and Lavrik, O.I. (2022). Monoterpene substituted thiazolidin-4-ones as novel TDP1 inhibitors: Synthesis, biological evaluation and docking. Bioorg. Med. Chem. Lett., 73.","DOI":"10.1016\/j.bmcl.2022.128909"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Khomenko, T.M., Zakharenko, A.L., Kornienko, T.E., Chepanova, A.A., Dyrkheeva, N.S., Artemova, A.O., Korchagina, D.V., Achara, C., Curtis, A., and Reynisson, J. (2023). New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119155"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/10\/1931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:05:39Z","timestamp":1760130339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/10\/1931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,12]]},"references-count":61,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["genes14101931"],"URL":"https:\/\/doi.org\/10.3390\/genes14101931","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,12]]}}}