Journal
MOLECULES
Volume 25, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/molecules25153496
Keywords
monoterpene; carene; topotecan; tyrosyl-DNA phosphodiesterase 1; synergy; TDP1gene knockout cells; inhibitor
Funding
- Russian Science Foundation [19-13-00040]
- Russian Foundation for Basic Research [19-415-540002]
- Russian Science Foundation [19-13-00040] Funding Source: Russian Science Foundation
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Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran11and 3-oxabicyclo [3.3.1]nonane12scaffolds 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(50)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 theTDP1gene 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 theTDP1gene knockout cells. For two TDP1 inhibitors,11hand12k, 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 for11hin 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.
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