Promising new inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 4- arylcoumarin and monoterpenoid moieties as components of complex antitumor therapy

Tatyana M. Khomenko, Alexandra L. Zakharenko, Arina A. Chepanova, Ekaterina S. Ilina, Olga D. Zakharova, Vasily I. Kaledin, Valeriy P. Nikolin, Nelly A. Popova, Dina V. Korchagina, Jóhannes Reynisson, Raina Chand, Daniel M. Ayine-tora, Jinal Patel, Ivanhoe K.H. Leung, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 μM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.

Original languageEnglish
Article number126
Number of pages21
JournalInternational Journal of Molecular Sciences
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

  • Cancer
  • Chemical space
  • Coumarin
  • DNA repair enzymes
  • Molecular modeling
  • Neoflavone
  • Tdp1 inhibitor
  • Topoisomerase 1 inhibitors
  • Topotecan
  • Tumor
  • EMPIRICAL SCORING FUNCTIONS
  • TOPOISOMERASE-I
  • BIOLOGICAL EVALUATION
  • chemical space
  • topotecan
  • CONSTITUENTS
  • coumarin
  • IDENTIFICATION
  • ENHANCE
  • neoflavone
  • molecular modeling
  • tumor
  • PROTEIN-LIGAND DOCKING
  • topoisomerase 1 inhibitors
  • RHABDOMYOSARCOMA
  • IRINOTECAN
  • cancer
  • COUMARIN DERIVATIVES

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