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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number3694
Number of pages13
JournalMolecules
Volume25
Issue number16
DOIs
Publication statusPublished - 13 Aug 2020

Keywords

  • DNA repair
  • Nucleosides
  • Tdp1 inhibition
  • Topotecan
  • Tyrosyl-DNA phosphodiesterase
  • PATHWAYS
  • POLY(ADP-RIBOSE)
  • POLYMERASE
  • TOPOISOMERASE-I
  • nucleosides
  • tyrosyl-DNA phosphodiesterase
  • DAMAGE RESPONSE
  • REPAIR
  • CAMPTOTHECIN
  • TDP1
  • DERIVATIVES
  • topotecan
  • COVALENT COMPLEXES

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