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

Tatyana M Khomenko,Olga I Lavrik,Olga D Zakharova,Jinal Patel,Konstantin P Volcho,Valeriy P Nikolin,Vasily I Kaledin,Arina A Chepanova,Ivanhoe K H Leung,Daniel M Ayine-Tora,Jóhannes Reynisson,Alexandra L Zakharenko,Dina V Korchagina,Nelly A Popova,Raina Chand,Ekaterina S Ilina,Nariman F Salakhutdinov

doi:10.3390/ijms21010126

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.

Highlights

Natural and synthetic coumarins (2H-chromen-2-one) demonstrate diverse biological activities, and are often considered as a privileged scaffold [1,2,3,4,5,6]
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
We report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin and monoterpenoid moieties

Summary

Introduction

Natural and synthetic coumarins (2H-chromen-2-one) demonstrate diverse biological activities, and are often considered as a privileged scaffold [1,2,3,4,5,6]. A large number of coumarin derivatives with high antitumor activity have been found in recent years [7,8,9,10,11,12,13,14,15,16,17,18]. One of the current approaches to increase the efficacy of clinically-established antitumor therapy is the inhibition of DNA repair enzymes that counteract the effect of DNA-damaging chemotherapy agents [23,24,25]. One of these important enzymes is tyrosyl-DNA phosphodiesterase 1 (Tdp1) [26]. Tdp reduces the impact of Top poisons, resulting in diminished DNA damage and reduced efficacy of this class of chemotherapeutic drugs

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