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Russian Journal of Bioorganic Chemistry

, Volume 45, Issue 6, pp 647–655 | Cite as

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. LavrikEmail author
Article
  • 4 Downloads

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.

Keywords:

tyrosyl-DNA phosphodiesterase 1 inhibitors topotecan octahydro-2H-chromene cytotoxicity 

Notes

ACKNOWLEDGMENTS

The authors would like to thank the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. The А-549 cell line was obtained from Collection of Vertebrate Cell Cultures of the Institute of Cytology, Russian Academy of Sciences, St. Petersburg.

FUNDING

This study was financially supported by the Russian Foundation for Basic Research (grant 19-44-543001 r_mol_a) and the Program of Fundamental Scientific Research of State Academies of Sciences for 2017–2020. (VI.57.1.2, 0309-2016-0001).

COMPLIANCE WITH ETHICAL STANDARDS

This article does not contain any studies involving animals or human participants performed by any of the authors.

Conflict of Interests

Authors declare that they have no conflicts of interests.

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Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • A. A. Chepanova
    • 1
  • N. S. Li-Zhulanov
    • 2
    • 3
  • A. S. Sukhikh
    • 3
    • 6
  • A. Zafar
    • 4
  • J. Reynisson
    • 5
  • A. L. Zakharenko
    • 1
  • O. D. Zakharova
    • 1
  • D. V. Korchagina
    • 2
  • K. P. Volcho
    • 2
    • 3
  • N. F. Salakhutdinov
    • 2
    • 3
  • O. I. Lavrik
    • 1
    • 3
    Email author
  1. 1.Institute of Chemical Biology and Fundamental Medicine, Russian Academy of SciencesNovosibirskRussia
  2. 2.Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of SciencesNovosibirskRussia
  3. 3.Novosibirsk State UniversityNovosibirskRussia
  4. 4.School of Chemical Sciences, University of AucklandAucklandNew Zealand
  5. 5.School of Pharmacy, Keele University, Hornbeam BuildingKeeleUnited Kingdom
  6. 6.Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of SciencesNovosibirskRussia

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