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

Anastasia O. Komarova, Mikhail S. Drenichev, Nadezhda S. Dyrkheeva, Irina V. Kulikova, Vladimir E. Oslovsky, Olga D. Zakharova, Alexandra L. Zakharenko, Sergey N. Mikhailov, Olga I. Lavrik

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1415-1429
Number of pages15
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
Issue number1
DOIs
Publication statusPublished - 7 Sep 2018

Keywords

  • Disaccharide nucleosides
  • TDP1 inhibitor
  • topotecan
  • tyrosyl-DNA phosphodiesterase 1
  • Humans
  • Cells, Cultured
  • Structure-Activity Relationship
  • Phosphodiesterase Inhibitors/chemical synthesis
  • Topotecan/chemical synthesis
  • Antineoplastic Agents/chemical synthesis
  • Phosphoric Diester Hydrolases/metabolism
  • Dose-Response Relationship, Drug
  • Nucleosides/chemical synthesis
  • Molecular Structure
  • Cell Proliferation/drug effects
  • Disaccharides/chemical synthesis
  • Drug Screening Assays, Antitumor
  • POLY(ADP-RIBOSE) POLYMERASE
  • HUMAN-CELLS
  • TOPOISOMERASE-I
  • SPINOCEREBELLAR ATAXIA
  • DERIVATIVES
  • REPAIR ENZYME
  • CRYSTAL-STRUCTURE
  • DAMAGE
  • TDP1
  • PYRIMIDINE NUCLEOSIDES

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