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
• DOI: 10.3390/molecules25153496
• ISSN: 1420-3049

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 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 TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.