{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T23:17:02Z","timestamp":1774653422385,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2020-773"],"award-info":[{"award-number":["075-15-2020-773"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3\u2032 end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23\u20130.40 \u03bcM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 \u2265 60 \u03bcM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan\u2019s cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This \u201cprotective\u201d effect from topotecan on non-cancerous cells requires further investigation.<\/jats:p>","DOI":"10.3390\/biom11070973","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T21:55:52Z","timestamp":1625176552000},"page":"973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition"],"prefix":"10.3390","volume":"11","author":[{"given":"Nadezhda S.","family":"Dyrkheeva","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 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, 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, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra L.","family":"Zakharenko","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina S.","family":"Ilina","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 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":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 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":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4174-9512","authenticated-orcid":false,"given":"J\u00f3hannes","family":"Reynisson","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-9324","authenticated-orcid":false,"given":"Konstantin P.","family":"Volcho","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suren M.","family":"Zakian","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 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, 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, 630090 Novosibirsk, Russia"},{"name":"Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0031-9422(02)00383-7","article-title":"Usnic acid","volume":"61","author":"Ingolfsdottir","year":"2002","journal-title":"Phytochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1080\/13543776.2018.1472239","article-title":"Usnic acid and its derivatives for pharmaceutical use: A patent review (2000\u20132017)","volume":"28","author":"Luzina","year":"2018","journal-title":"Expert Opin. 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