Promising new inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 4- arylcoumarin and monoterpenoid moieties as components of complex antitumor therapy
Loading...
Citations
Web of Science:
Altmetric:
Altmetric::
Download
Associated Records
File Licence
Editors
Date
2020-01-01
Source Title
International Journal of Molecular Sciences
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI
Melbourne Authors
Affiliation
School of Chemistry
Document Type
Journal Article
Subject Code
Citation
Khomenko, T. M., Zakharenko, A. L., Chepanova, A. A., Ilina, E. S., Zakharova, O. D., Kaledin, V. I., Nikolin, V. P., Popova, N. A., Korchagina, D. V., Reynisson, J., Chand, R., Ayine-tora, D. M., Patel, J., Leung, I. K. H., Volcho, K. P., Salakhutdinov, N. F. & Lavrik, O. I. (2020). 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, 21 (1), https://doi.org/10.3390/ijms21010126.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
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.