1. Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1
- Author
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Olga D. Zakharova, A.A. Malakhova, Nariman F. Salakhutdinov, Jóhannes Reynisson, Alexandra L. Zakharenko, Sergey P. Medvedev, Alexander Yu. Sidorenko, Irina V. Il'ina, Dina V. Korchagina, Suren M. Zakian, Raina Chand, N.S. Li-Zhulanov, Nadezhda S Dyrkheeva, Konstantin P. Volcho, Arina A Chepanova, Ekaterina S Ilina, Daniel M Ayine-Tora, and Olga I. Lavrik
- Subjects
Phosphodiesterase Inhibitors ,Pharmaceutical Science ,synergy ,Q1 ,01 natural sciences ,Analytical Chemistry ,Gene Knockout Techniques ,Drug Discovery ,Cytotoxic T cell ,TDP1 gene knockout cells ,Bicyclic Monoterpenes ,chemistry.chemical_classification ,0303 health sciences ,Phosphodiesterase ,Drug Synergism ,Tyrosyl-DNA Phosphodiesterase 1 ,inhibitor ,tyrosyl-DNA phosphodiesterase 1 ,Biochemistry ,Chemistry (miscellaneous) ,Molecular Medicine ,TDP1 ,Signal Transduction ,carene ,Cell Survival ,Article ,lcsh:QD241-441 ,Inhibitory Concentration 50 ,03 medical and health sciences ,topotecan ,lcsh:Organic chemistry ,RZ ,Humans ,Physical and Theoretical Chemistry ,Gene knockout ,Cell Proliferation ,030304 developmental biology ,Phosphoric Diester Hydrolases ,010405 organic chemistry ,Organic Chemistry ,HCT116 Cells ,R1 ,0104 chemical sciences ,HEK293 Cells ,Enzyme ,chemistry ,Cell culture ,Drug Design ,Cancer cell ,CRISPR-Cas Systems ,monoterpene ,RC ,HeLa Cells - Abstract
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 &mu, M. 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 &minus, /&minus, 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.
- Published
- 2020