biostudies-literatureIl'ina IVRussian Foundation for Basic ResearchRussian Science FoundationE3496https://www.ebi.ac.uk/biostudies/studies/S-EPMC7436013biostudies-literatureUnknown25(15)Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran <b>11</b> and 3-oxabicyclo [3.3.1]nonane <b>12</b> scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC₅₀ value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the <i>TDP1</i> gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytMolecules (Basel, Switzerland)Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1.PMC743601319-13-0004019-415-540002Reynisson JLavrik OIChepanova AAChand RIl'ina IVZakharenko ALLi-Zhulanov NSDyrkheeva NSIlina ESMedvedev SPSalakhutdinov NFAyine-Tora DMSidorenko AYVolcho KPMalakhova AAZakharova ODZakian SMKorchagina DVfalseDesign, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1.Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran <b>11</b> and 3-oxabicyclo [3.3.1]nonane <b>12</b> scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC₅₀ value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the <i>TDP1</i> gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cyt2020-01-01T00:00:00Z2020 Jul2026-04-30T07:42:36.517Z2026-04-07T15:54:46.729ZS-EPMC74360133275199710.3390/molecules25153496