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Novel antimitotic agents related to tubuloclustin: synthesis and biological evaluation

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Abstract

Tubuloclustin [N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine], a highly cytotoxic anti-tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of tubulin clusters of unique morphology. Three series of antimitotic agents related to tubuloclustin were designed and synthesized in order to enhance the molecular diversity of “tubuloclustin-like” family of compounds. The series of compounds with modified adamantane moiety was highly potent in cytotoxic effect on human lung carcinoma A549 cells (EC50 = 6–400 nM) and was active in affecting the microtubule arrays and induction of strong tubulin clusterization. In two other sets of compounds, the colchicine moiety of tubuloclustin was replaced by podophyllotoxin or combretastatin A-4. All combretastatin A-4 derivatives displayed noticeable cytotoxic activity (\(\hbox {EC}50=0.8{-}1.6\,\upmu \hbox {M}\)) but their effect on microtubules depended on the position of the linker attachment. Podophyllotoxin derivatives were also toxic to A549 cells (\(\hbox {EC}50=0.38{-}0.50\,\upmu \hbox {M}\)) and caused both microtubule depolymerization and some tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine, podophyllotoxin and combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.

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Acknowledgements

The work was supported by Russian Foundation for Basic Research (project 15-03-04894), Russian Academy of Sciences and by the German organization DAAD (German Academic Exchange Service) in the frame of a Scientific Cooperation Agreement between Moscow and Rostock Universities.

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Authors and Affiliations

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

    Olga N. Zefirova, Evgeniya V. Nurieva, Vladimir V. Gogol, Nikolay A. Zefirov, Dmitrii V. Shishov & Nikolay S. Zefirov

  2. Institute of Physiologically Active Compounds, Severnyi Proezd, 1, Chernogolovka, Moscow Region, Russian Federation, 142432

    Olga N. Zefirova

  3. Institute of Biological Sciences, University of Rostock, 18059, Rostock, Germany

    Birgit Wobith, Andrei V. Ogonkov & Sergei A. Kuznetsov

Authors
  1. Olga N. Zefirova
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  2. Evgeniya V. Nurieva
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  3. Birgit Wobith
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  4. Vladimir V. Gogol
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  5. Nikolay A. Zefirov
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  6. Andrei V. Ogonkov
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  7. Dmitrii V. Shishov
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  8. Nikolay S. Zefirov
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  9. Sergei A. Kuznetsov
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Corresponding author

Correspondence to Evgeniya V. Nurieva.

Additional information

During final preparation of this manuscript Nikolay S. Zefirov sadly died. This paper is dedicated to his memory.

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Appendix: Supplementary materials

Appendix: Supplementary materials

Supplementary data contain the pictures of computer overlay of the structures, additional experimental data and copies of \(^{1}\hbox {H}\) and \(^{13}\hbox {C NMR}\) spectra of synthesized compounds.

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Zefirova, O.N., Nurieva, E.V., Wobith, B. et al. Novel antimitotic agents related to tubuloclustin: synthesis and biological evaluation. Mol Divers 21, 547–564 (2017). https://doi.org/10.1007/s11030-017-9739-6

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  • DOI: https://doi.org/10.1007/s11030-017-9739-6

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