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Role of structural components of the 2-methoxyestradiol—chlorambucil conjugate in microtubule stabilization

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Abstract

The conjugate of 2-methoxyestradiol, a ligand for the cell protein tubulin, with two molecules of chlorambucil, known as a DNA-alkylating agent, is capable of blocking the dynamics of tubulin-based microtubules at concentrations of 10–100 µmol L−1, by stabilizing them without changing their structure. Three analogs of this conjugate, which do not contain chloroethylamino and/or methoxy groups at C(2), were synthesized. At these concentrations, these analogs have another, inhibitory or combined, effect on the microtubule polymerization. Based on the molecular modeling results, the binding site of the initial conjugate in tubulin was proposed.

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Authors and Affiliations

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

    N. A. Zefirov, A. V. Mamaeva, E. R. Milaeva & O. N. Zefirova

  2. Institute of Physiologically Active Compounds, Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnyi proezd, 142432, Chernogolovka, Moscow Region, Russian Federation

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

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

    P. D. Korotkova

Authors
  1. N. A. Zefirov
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  2. P. D. Korotkova
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  3. E. F. Shevtsova
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  4. P. N. Shevtsov
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  5. A. V. Mamaeva
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  6. E. R. Milaeva
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  7. O. N. Zefirova
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Corresponding author

Correspondence to O. N. Zefirova.

Additional information

The investigations were performed using facilities of the Multiple-access Center of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences (IPAC RAS).

This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation within the framework of the state assignment (Program No. 121021000105-7). The biological testing of compounds was carried out within the framework of the state assignment to the IPAC RAS, 2022 (FFSN-2021-0005).

All experiments on animals were performed in compliance with the regulations of the Russian Federation on the ethical principles and guidelines for the use of animals for scientific purposes (GOST 33044-2014) and in accordance with the Order No. 199n of the Ministry of Health of the Russian Federation, January 1, 2016.

The authors declare no competing interests.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2519–2524, November, 2022.

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Zefirov, N.A., Korotkova, P.D., Shevtsova, E.F. et al. Role of structural components of the 2-methoxyestradiol—chlorambucil conjugate in microtubule stabilization. Russ Chem Bull 71, 2519–2524 (2022). https://doi.org/10.1007/s11172-022-3682-0

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  • DOI: https://doi.org/10.1007/s11172-022-3682-0

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