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

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1415-1429. doi: 10.1080/14756366.2018.1509210.

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.

Keywords: Disaccharide nucleosides; TDP1 inhibitor; topotecan; tyrosyl-DNA phosphodiesterase 1.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disaccharides / chemical synthesis
  • Disaccharides / chemistry
  • Disaccharides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Structure-Activity Relationship
  • Topotecan / chemical synthesis
  • Topotecan / chemistry
  • Topotecan / pharmacology*

Substances

  • Antineoplastic Agents
  • Disaccharides
  • Nucleosides
  • Phosphodiesterase Inhibitors
  • Topotecan
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human

Grants and funding

Biological part of the work (determination of half-maximal inhibitory concentrations (IC50) on a double-stranded DNA, inhibition constants (KI), the effect of inhibitors on cell growth and viability and their effect in combination with topotecan) was supported by Russian Scientific Foundation grant 14–24-00038. Chemical part of the work (the synthesis and characterisation of disaccharide nucleosides) and determination of IC50 on a single-stranded DNA were supported by Russian Scientific Foundation grant 17–74-10057.