{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:15:30Z","timestamp":1785413730344,"version":"3.56.0"},"reference-count":89,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"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":["25-73-20089"],"award-info":[{"award-number":["25-73-20089"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25-73-20089"],"award-info":[{"award-number":["25-73-20089"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC50 values in the submicromolar to low micromolar range (0.8\u20133.2 \u03bcM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC50 values ranged from 1.1 to 23.3 \u03bcM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy.<\/jats:p>","DOI":"10.3390\/ijms27146421","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Biological Evaluation of TDP1 Inhibitors Based on Coumarin and Monoterpenoid Fragments Conjoined by Heterocyclic Moieties"],"prefix":"10.3390","volume":"27","author":[{"given":"Dmitriy","family":"Tsypyshev","sequence":"first","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5702-3595","authenticated-orcid":false,"given":"Tatyana","family":"Khomenko","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5427-9786","authenticated-orcid":false,"given":"Tatyana","family":"Kornienko","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Zakharenko","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Komarova","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5387-8365","authenticated-orcid":false,"given":"Vyacheslav","family":"Krasnov","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Soldatova","sequence":"additional","affiliation":[{"name":"Tomsk Polytechnic University, Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9713-1290","authenticated-orcid":false,"given":"Pavel","family":"Postnikov","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8248-4218","authenticated-orcid":false,"given":"Suat","family":"Sari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara 06230, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-9324","authenticated-orcid":false,"given":"Konstantin","family":"Volcho","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5980-8889","authenticated-orcid":false,"given":"Olga","family":"Lavrik","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariman","family":"Salakhutdinov","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nrc1977","article-title":"Topoisomerase I Inhibitors: Camptothecins and Beyond","volume":"6","author":"Pommier","year":"2006","journal-title":"Nat. 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