Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy

A. A. Chepanova, N. S. Li-Zhulanov, A. S. Sukhikh, A. Zafar, J. Reynisson, A. L. Zakharenko, O. D. Zakharova, D. V. Korchagina, K. P. Volcho, N. F. Salakhutdinov, O. I. Lavrik

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the important DNA repair enzymes responsible for the repair of DNA damage caused by anticancer drugs, such as topotecan. In this regard, enzyme activity is one of the possible causes of tumor resistance to chemotherapy, and the use of inhibitors of this enzyme is considered as a promising adjuvant therapy. We have obtained a number of new isomeric naphthyl derivatives of thiophenyl octahydro-2H-chromene, the structure of one of which is confirmed by X-ray structural analysis. Based on molecular modeling data, the structure of the ligand-Tdp1 complex has been proposed. All compounds obtained inhibit Tdp1 at a concentration of about 2 μM. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.

Original languageEnglish
Pages (from-to)647-655
Number of pages9
JournalRussian Journal of Bioorganic Chemistry
Volume45
Issue number6
DOIs
Publication statusPublished - 1 Nov 2019

Keywords

  • cytotoxicity
  • octahydro-2H-chromene
  • topotecan
  • tyrosyl-DNA phosphodiesterase 1 inhibitors
  • ASSAY
  • EMPIRICAL SCORING FUNCTIONS
  • IDENTIFICATION
  • ENHANCE
  • PROTEIN-LIGAND DOCKING
  • TDP1
  • IN-VIVO
  • BIOLOGICAL EVALUATION
  • BINDING

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