Skip to main content
SpringerLink
Log in

“Triple” mutual prodrug based on 2-methoxyestradiol: synthesis and biotesting in vitro

  • Full Articles
  • Published:
Russian Chemical Bulletin Aims and scope

Abstract

Ester of the tubulin ligand, 2-methoxyestradiol, with two molecules of DNA alkylating agent chlorambucil was proposed as a “triple” mutual prodrug for blocking rapid metabolism of the initial steroid. The target conjugate was synthesized via the Steglich esterification. The biotesting results demonstrate a very low cytotoxicity to cancer and conditionally normal cells (EC50 ~100 μmol L−1), a weak inhibition of the cell growth (A549: 20%/48 h), no stimulation of apoptosis, and no influence on the microtubule morphology of human lung carcinoma A549 cells and the ability to increase the rate of microtubule assembling. The sharp distinction of these properties from those for the initial 2-methoxyestradiol and chlorambucil molecules indicates that the synthesized prodrug is stable in vitro and demonstrates an expediency of its further testing in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. C. G. Wermuth, C. R. Ganellin, P. Lindberg, L. A. Mitscher, Pure Appl. Chem., 1998, 70, 1129.

    Article  CAS  Google Scholar 

  2. B. S. Kumar, D. S. Raghuvanshi, M. Hasanain, S. Alam, J. Sarkar, K. Mitra, F. Khan, A. S. Negi, Steriods, 2016, 110, 9.

    Article  CAS  Google Scholar 

  3. N. A. Zefirov, O. N. Zefirova, Russ. tJ. Org. Chem., 2015, 51, 1207.

    Article  CAS  Google Scholar 

  4. M. P. Leese, F. L. Jourdan, M. R. Major, W. Dohle, E. Hamel, E. Ferrandis, A. Fiore, Ph. G. Kasprzyk, B. V. L. Potter, ChemMedChem, 2014, 9, 85.

    Article  CAS  Google Scholar 

  5. E. V. Nurieva, N. A. Zefirov, A. V. Mamaeva, Y. K. Grishin, S. A. Kuznetsov, O. N. Zefirova, Mendeleev Commun., 2017, 27, 240.

    Article  CAS  Google Scholar 

  6. S. Kambhampati, R. A. Rajewski, M. Tanol, I. Haque, A. Das, S. Banerjee, S. Jha, D. Burns, E. Borrego-Diaz, P. J. Van Veldhuizen, S. K. Banerjee, Mol. Cancer Ther., 2013, 12, 255.

    Article  CAS  Google Scholar 

  7. Y. Chen, Y. Jia, W. Song, L. Zhang, Front. Pharmacol., 2018, 9, 1453.

    Article  CAS  Google Scholar 

  8. A. Gupta, P. Saha, C. Descoteaux, V. Leblanc, E. Asselin, G. Berube, Bioorg. Med. Chem. Lett., 2010, 20, 1614.

    Article  CAS  Google Scholar 

  9. E. V. Nurieva, N. A. Zefirov, A. V. Mamaeva, B. Wobith, S. A. Kuznetsov, O. N. Zefirova, Russ. Chem. Bull., 2018, 67, 688.

    Article  CAS  Google Scholar 

  10. T. Mosmann, J. Immunol. Meth., 1983, 65, 55.

    Article  CAS  Google Scholar 

  11. N. A. Zefirov, E. A. Lavrushkina, S. A. Kuznetsov, O. N. Zefirova, Biomed. Khim. [Biomedical Chemistry], 2019, 65, 86 (in Russian).

    Article  CAS  Google Scholar 

  12. R. K. Singh, D. N. Prasad, T. R. Bhardwaj, Med. Chem. Res. 2015, 24, 1534.

    Article  CAS  Google Scholar 

  13. Zh. Wang, D. Yang, A. K. Mohanakrishnan, Ph. E. Fanwick, P. Nampoothiri, E. Hamel, M. Cushman, J. Med. Chem., 2000, 43, 2419.

    Article  CAS  Google Scholar 

  14. M. D. Wittman, J. F. Kadow, D. M. Vyas, F. L. Lee, W. C. Rose, B. H. Long, C. Fairchild, K. Johnston, Bioorg. Med. Chem. Lett., 2001, 11, 811.

    Article  CAS  Google Scholar 

  15. B. Coggiola, F. Pagliai, G. Allegrone, A. A. Genazzani, G. C. Tron, Bioorg. Med. Chem. Lett., 2005, 15, 3551.

    Article  CAS  Google Scholar 

  16. S. O. Bachurin, E. F. Shevtsova, G. F. Makhaeva, V. V. Grigoriev, N. P. Boltneva, N. V. Kovaleva, S. V. Lushchekina, P. N. Shevtsov, M. E. Neganova, O. M. Redkozubova, E. V. Bovina, A. V. Gabrelyan, V. P. Fisenko, V. P. Sokolov, A. Y. Aksinenko, V. Echeverria, G. E. Barreto, G. Aliev, Sci. Rep., 2017, 7, 45627.

    Article  CAS  Google Scholar 

  17. P. N. Shevtsov, E. F. Shevtsova, G. Sh. Burbaeva, S. O. Bachurin, Bull. Exp. Biol. Med., 2006, 141, 265.

    Article  CAS  Google Scholar 

  18. O. N. Zefirova, H. Lemcke, M. Lantow, E. V. Nurieva, B. Wobith, G. E. Onishchenko, A. Hoenen, G. Griffiths, N. S. Zefirov, S. A. Kuznetsov, ChemBioChem, 2013, 14, 1444.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, M. V. Lomonosov Moscow State University, Build. 3, 1 Leninskie Gory, 119991, Moscow, Russian Federation

    E. A. Lavrushkina, N. A. Zefirov & O. N. Zefirova

  2. Department of Fundamental Medicine, M. V. Lomonosov Moscow State University, Build. 1, 27 Lomonosovsky prosp., 119991, Moscow, Russian Federation

    V. M. Shibilev

  3. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severnyi proezd, 142432, Chernogolovka, Moscow Region, Russian Federation

    N. A. Zefirov, E. F. Shevtsova, P. N. Shevtsov & O. N. Zefirova

  4. Institute of Biological Sciences, University of Rostock, D-18059, Rostock, Germany

    S. A. Kuznetsov

Authors
  1. E. A. Lavrushkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. M. Shibilev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. A. Zefirov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. F. Shevtsova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. N. Shevtsov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. A. Kuznetsov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. O. N. Zefirova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. N. Zefirova.

Additional information

The authors are grateful to D. A. Skvortsov for help in the work and to the German Academic Exchange Service (DAAD). Some works on the evaluation of the effect of the compounds on tubulin aggregation were carried out in terms in the State Task of the Ministry of Science and Higher Education (Theme No. 0090-2017-0019) using the Center for Collective Use of the Institute of Physiologically Active Compounds (Russian Academy of Sciences).

This work was financially supported by the Russian Foundation for Basic Research (Project No. 18-03-00524).

Universität Rostock, Institut für Zellbiologie und Bio systemtechnik, Albert-Einstein-Str. 3, D-18059 Rostock, Deutschland.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0558–0562, March, 2020.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lavrushkina, E.A., Shibilev, V.M., Zefirov, N.A. et al. “Triple” mutual prodrug based on 2-methoxyestradiol: synthesis and biotesting in vitro. Russ Chem Bull 69, 558–562 (2020). https://doi.org/10.1007/s11172-020-2798-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11172-020-2798-3

Keywords

Search

Navigation