Il'ina, IV, Dyrkheeva, NS, Zakharenko, AL, Sidorenko, AY, Li-Zhulanov, NS, Korchagina, DV, Chand, R, Ayine-Tora, DM, Chepanova, AA, Zakharova, OD, Ilina, ES, Reynisson, J ORCID: https://orcid.org/0000-0003-4174-9512, Malakhova, AA, Medvedev, SP, Zakian, SM, Volcho, KP, Salakhutdinov, NF and Lavrik, OI (2020) Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules, 25 (15).

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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 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.

Item Type: Article
Additional Information: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Uncontrolled Keywords: monoterpene; carene; topotecan; tyrosyl-DNA phosphodiesterase 1; synergy; TDP1 gene knockout cells; inhibitor
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
R Medicine > RZ Other systems of medicine
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 17 Aug 2020 13:07
Last Modified: 01 Sep 2020 10:20
URI: https://eprints.keele.ac.uk/id/eprint/8561

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