Inhibition of tyrosyl-DNA phosphodiesterase 1 by lipophilic pyrimidine nucleosides

Alexandra L. Zakharenko, Mikhail S. Drenichev, Nadezhda S. Dyrkheeva, Georgy A. Ivanov, Vladimir E. Oslovsky, Ekaterina S. Ilina, Irina A. Chernyshova, Olga I. Lavrik, Sergey N. Mikhailov

Результат исследования: Научные публикации в периодических изданияхстатья

Аннотация

Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose) polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC50) in the lower micromolar and submicromolar range. 2′,3′,5′-Tri-Obenzoyl- 5-iodouridinemanifested the strongest inhibitory effect on Tdp1 (IC50 = 0.6 μM). Adecrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC50 > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1mMsubstances was 50-100%). Several O-benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells.

Язык оригиналаанглийский
Номер статьи3694
ЖурналMolecules
Том25
Номер выпуска16
DOI
СостояниеОпубликовано - 13 авг 2020

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    Zakharenko, A. L., Drenichev, M. S., Dyrkheeva, N. S., Ivanov, G. A., Oslovsky, V. E., Ilina, E. S., Chernyshova, I. A., Lavrik, O. I., & Mikhailov, S. N. (2020). Inhibition of tyrosyl-DNA phosphodiesterase 1 by lipophilic pyrimidine nucleosides. Molecules, 25(16), [3694]. https://doi.org/10.3390/molecules25163694