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

• Published in: International journal of molecular sciences 2019-12, Vol.21 (1), p.126
• Main Authors: Khomenko, Tatyana M, Zakharenko, Alexandra L, Chepanova, Arina A, Ilina, Ekaterina S, Zakharova, Olga D, Kaledin, Vasily I, Nikolin, Valeriy P, Popova, Nelly A, Korchagina, Dina V, Reynisson, Jóhannes, Chand, Raina, Ayine-Tora, Daniel M, Patel, Jinal, Leung, Ivanhoe K H, Volcho, Konstantin P, Salakhutdinov, Nariman F, Lavrik, Olga I
• Format: Article
• Language: English
• Subjects: Animals; Antitumor activity; Ascites; Cancer therapies; Carcinoma, Krebs 2 - drug therapy; Carcinoma, Krebs 2 - enzymology; Carcinoma, Krebs 2 - pathology; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - pathology; Chromatography; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Enzymes; Experiments; Female; Humans; Inhibitors; Irinotecan; Male; MCF-7 Cells; Mice; Monoterpenes - chemical synthesis; Monoterpenes - chemistry; Monoterpenes - pharmacology; Natural products; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Phosphodiesterase; Phosphodiesterase I; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Structure-Activity Relationship; Topotecan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010126

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 IC values in the submicromolar range. In vivo experiments with mice revealed that compound (IC 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.