Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

Journal of Enzyme Inhibition and Medicinal Chemistry

Sergey N. Mikhailov¹  Mikhail S. Drenichev¹  Vladimir E. Oslovsky¹  Irina V. Kulikova¹  Alexandra L. Zakharenko²  Olga D. Zakharova²  Nadezhda S. Dyrkheeva²  Anastasia O. Komarova³  Olga I. Lavrik³ 

[1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federatio;Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation;Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation;Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation;

关键词: Disaccharide nucleosides;    tyrosyl-DNA phosphodiesterase 1;    TDP1 inhibitor;    topotecan;   

DOI  :  10.1080/14756366.2018.1509210

来源: publisher

【 摘 要 】

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC50 values (half-maximal inhibitory concentration) in 0.4–18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan. Moreover, kinetic parameters of the enzymatic reaction and fluorescence anisotropy were measured using different types of DNA-biosensors to give a sufficient insight into the mechanism of inhibitor’s action.

【 授权许可】

CC BY