Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2-p53 Interaction

Molecules. 2019 Aug 10;24(16):2909. doi: 10.3390/molecules24162909.

Abstract

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.

Keywords: MDM2–p53 inhibition; indane derivatives; isoxazolidines; spirooxindoles.

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma of Lung* / pathology
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Microwaves
  • Molecular Structure
  • Neuroblastoma* / drug therapy
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / pathology
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Spiro Compounds* / chemical synthesis
  • Spiro Compounds* / chemistry
  • Spiro Compounds* / pharmacology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Spiro Compounds
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2