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

Int J Mol Sci. 2019; 
Khomenko TM1, Zakharenko AL2, Chepanova AA2, Ilina ES2, Zakharova OD2, Kaledin VI3, Nikolin VP3, Popova NA3,4, Korchagina DV1, Reynisson J5, Chand R6, Ayine-Tora DM6, Patel J6, Leung IKH6, Volcho KP1,4, Salakhutdinov NF1,4, Lavrik OI2,4,7.
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Bacterial Expression System Synthetic DNA encoding human Tdp1 (residues 149-608) was cloned into pET-28a (+) (GenScript), which was then transformed into Escherichia coli BL21 (DE3) for recombinant protein production. Get A Quote

摘要

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 ascite... More

关键词

DNA repair enzymes; Tdp1 inhibitor; cancer; chemical space; coumarin; molecular modeling; neoflavone; topoisomerase 1 inhibitors; topotecan; tumor