Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors

Oksana V. Salomatina, Irina I. Popadyuk, Alexandra L. Zakharenko, Olga D. Zakharova, Dmitriy S. Fadeev, Nina I. Komarova, Jóhannes Reynisson, H. John Arabshahi, Raina Chand, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme.

Original languageEnglish
Article number679
Number of pages19
JournalMolecules
Volume23
Issue number3
DOIs
Publication statusPublished - 17 Mar 2018

Keywords

  • Amide
  • Cancer
  • Chenodeoxycholic acid
  • Deoxycholic acid
  • Molecular modelling
  • Tdp1 inhibitor
  • Tumor
  • Ursodeoxycholic acid
  • Virtual screening
  • HCT116 Cells
  • Humans
  • Bile Acids and Salts/chemical synthesis
  • Phosphodiesterase Inhibitors/chemical synthesis
  • Phosphoric Diester Hydrolases/metabolism
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Drug Evaluation, Preclinical
  • Binding Sites
  • Niacinamide/analogs & derivatives
  • Tryptamines/chemical synthesis
  • STRAND BREAK REPAIR
  • virtual screening
  • HUMAN-CELLS
  • TOPOISOMERASE-I
  • deoxycholic acid
  • ursodeoxycholic acid
  • CAMPTOTHECIN
  • BIOLOGICAL EVALUATION
  • CHEMISTRY
  • molecular modelling
  • DAMAGE
  • ANTICANCER
  • amide
  • TDP1
  • tumor
  • cancer
  • BINDING
  • chenodeoxycholic acid

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