Design and synthesis of new inhibitors of p53–MDM2 interaction with a chalcone scaffold

Daniela Pereira, Raquel T. Lima, Andreia Palmeira, Hugo Seca, Joana Soares, Sara Gomes, Liliana Raimundo, Claudia Maciel, Madalena Pinto, Emília Sousa, M. Helena Vasconcelos, Lucília Saraiva, Honorina Cidade

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Abstract

The virtual screening of a library of chalcone derivatives led us to the identification of potential new MDM2 ligands. The chalcones with the best docking scores obeying the Lipinski rule of five were subsequently prepared by base-catalyzed aldol reactions. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast-based screening assay. Using this approach two chalcones (3 and 4) were identified as putative small molecule inhibitors of p53–MDM2 interaction. The activity of both chalcones was further investigated in a panel of human tumor cells. Chalcones 3 and 4 revealed a pronounced tumor cell growth inhibitory effect on tumor cell lines. Additionally, chalcone 4 caused alterations in the cell cycle profile, induced apoptosis and increased the levels of p53, p21 and PUMA proteins in NCI-H460 cells. Computational docking studies allowed to predict that, like nutlin-3A (a well-known small-molecule inhibitor of p53–MDM2 interaction), chalcones 3 and 4 bind to the p53-binding site of MDM2. The results here presented will be valuable for the structure-based design of novel and potent p53–MDM2 inhibitors.

Original languageEnglish
Pages (from-to)4150-4161
Number of pages12
JournalArabian Journal of Chemistry
Volume12
Issue number8
Early online date3 May 2019
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Chalcones
  • Docking
  • In vitro antitumor activity
  • p53–MDM2 interaction inhibitors

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    Pereira, D., Lima, R. T., Palmeira, A., Seca, H., Soares, J., Gomes, S., Raimundo, L., Maciel, C., Pinto, M., Sousa, E., Helena Vasconcelos, M., Saraiva, L., & Cidade, H. (2019). Design and synthesis of new inhibitors of p53–MDM2 interaction with a chalcone scaffold. Arabian Journal of Chemistry, 12(8), 4150-4161. https://doi.org/10.1016/j.arabjc.2016.04.015