Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/ijms21010126
Keywords
coumarin; neoflavone; DNA repair enzymes; Tdp1 inhibitor; cancer; tumor; topotecan; topoisomerase 1 inhibitors; molecular modeling; chemical space
Funding
- Russian Science Foundation [19-13-00040]
- Russian State funded budget project of ICBFM SB RAS [AAAA-A17-117020210022-4]
- Russian Science Foundation [19-13-00040] Funding Source: Russian Science Foundation
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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 mu M) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.
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