The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Arina A. Chepanova, Evgenii S. Mozhaitsev, Aldar A. Munkuev, Evgeniy V. Suslov, Dina V. Korchagina, Olga D. Zakharova, Alexandra L. Zakharenko, Jinal Patel, Daniel M. Ayine-Tora, Jóhannes Reynisson, Ivanhoe K.H. Leung, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 μM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 μM concentration, displaying strong synergism. This effect was only seen for 46a (IC50-3.3 μM) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

Original languageEnglish
Article number2767
JournalApplied Sciences (Switzerland)
Volume9
Issue number13
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • A-549 lung adenocarcinoma cell line l
  • Chemical space
  • Fluorescence biosensor assay
  • Intrinsic tryptophan fluorescence binding assay
  • Molecular modelling
  • Synergy
  • Thermal shift assay
  • Topoisomerase 1
  • Topotecan
  • synergy
  • EMPIRICAL SCORING FUNCTIONS
  • fluorescence biosensor assay
  • REPAIR
  • FRAGMENTS
  • intrinsic tryptophan fluorescence binding assay
  • CAMPTOTHECIN
  • BIOLOGICAL EVALUATION
  • chemical space
  • DERIVATIVES
  • topotecan
  • MECHANISM
  • molecular modelling
  • thermal shift assay
  • PROTEIN-LIGAND DOCKING
  • TDP1
  • TOPOISOMERASE-I INHIBITORS

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