Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Reynisson

Abstract

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 µM) 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.

Citation

Reynisson. (2019). Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. International Journal of Molecular Sciences, https://doi.org/10.3390/ijms21010126

• Acceptance Date: Dec 20, 2019
• Publication Date: Dec 23, 2019
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Publisher: MDPI
• DOI: https://doi.org/10.3390/ijms21010126
• Keywords: DNA repair enzymes, Tdp1 inhibitor, cancer, chemical space, coumarin, molecular modeling, neoflavone, topoisomerase 1 inhibitors, topotecan, tumor
• Publisher URL: http://doi.org/10.3390/ijms21010126