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: 3-Carene; Aldehydes; Apoptosis; Bicyclic Monoterpenes - chemistry; Biotechnology; Cancer; carene; Cell Proliferation - drug effects; Cell Survival - drug effects; Clay; CRISPR; 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; Inhibitors; Inhibitory Concentration 50; Isomerization; monoterpene; Phosphodiesterase; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Sensitizing; Side effects; Signal Transduction - drug effects; Synergistic effect; synergy; TDP1 gene knockout cells; Topotecan; Topotecan - pharmacology; Tumor cell lines; tyrosyl-DNA phosphodiesterase 1; monoterpene; synergy; carene; inhibitor; TDP1 gene knockout cells; tyrosyl-DNA phosphodiesterase 1; topotecan
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25153496

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran
and 3-oxabicyclo [3.3.1]nonane
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 IC
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
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
gene knockout cells. For two TDP1 inhibitors,
and
, 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
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.