Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 15; p. 3496
• Main Authors: Il’ina, Irina V., Dyrkheeva, Nadezhda S., Zakharenko, Alexandra L., Sidorenko, Alexander Yu, Li-Zhulanov, Nikolay S., Korchagina, Dina V., Chand, Raina, Ayine-Tora, Daniel M., Chepanova, Arina A., Zakharova, Olga D., Ilina, Ekaterina S., Reynisson, Jóhannes, Malakhova, Anastasia A., Medvedev, Sergey P., Zakian, Suren M., Volcho, Konstantin P., Salakhutdinov, Nariman F., Lavrik, Olga I.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.07.2020; MDPI
• Subjects: Apoptosis; Bicyclic Monoterpenes - chemistry; Cancer; carene; Cell Proliferation - drug effects; Cell Survival - drug effects; Clay; CRISPR-Cas Systems; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug Design; Drug Synergism; Enzymes; Gene Knockout Techniques; HCT116 Cells; HEK293 Cells; HeLa Cells; Humans; Inhibitory Concentration 50; monoterpene; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Signal Transduction - drug effects; synergy; TDP1 gene knockout cells; topotecan; Topotecan - pharmacology; tyrosyl-DNA phosphodiesterase 1; monoterpene; synergy; carene; inhibitor; TDP1 gene knockout cells; tyrosyl-DNA phosphodiesterase 1; topotecan

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed...