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Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors

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Abstract

p53-MDM2/MDMX interaction inhibitors represent the prospective agents for targeted anticancer therapy in tumors expressing wild-type p53 protein. Imidazoline-based MDM2-targeted inhibitors of such type, nutlins, contain halogen-substituted phenyl rings, which dramatically decrease the solubility of compounds in water. The addition of suitable hydrophilic substituents in benzene rings and to imidazoline nitrogen can improve the compound’s water solubility. In this study, we have synthesized novel hydrophilic cis-2,4,5-tris(alkoxyphenyl)imidazolines and studied the influence of N-sulfonyl substituent on protein-protein interaction compared to unsubstituted alkoxy-compounds. The biological activity of the obtained compounds was studied using Western blot analysis on A549, RKO and SH-SY5Y cancer cell lines. It was found that the derivatives are able to inhibit MDM2/MDMX-p53 interaction, promote p53 stabilization and induce p21 expression in the concentrations from 500 nM.

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Acknowledgements

Synthetic part of this study was supported by the Russian Foundation for Basic Research (Projects No. 20-03-00915) (Figs. 1–3) and the biological part was supported by the grant from the Russian Science Foundation (Projects 17-75-20102) (Figs. 4–6).

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Author notes

  1. These authors contributed equally: Daniil R. Bazanov, Nikolay V. Pervushin

Authors and Affiliations

  1. Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory, 1, Moscow, 119992, Russia

    Daniil R. Bazanov, Michael D. Tsymliakov, Anita I. Maksutova, Sergey E. Sosonyuk & Natalia A. Lozinskaya

  2. Department of Medicine, M.V. Lomonosov Moscow State University, Leninskie Gory, 1, Moscow, 119992, Russia

    Nikolay V. Pervushin, Egor V. Savin & Gelina S. Kopeina

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  1. Daniil R. Bazanov
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Correspondence to Gelina S. Kopeina or Natalia A. Lozinskaya.

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Bazanov, D.R., Pervushin, N.V., Savin, E.V. et al. Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors. Med Chem Res 30, 2216–2227 (2021). https://doi.org/10.1007/s00044-021-02802-w

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