Inhibition of p53-Murine Double Minute 2 (MDM2) Interactions with 3,3'-Spirocyclopentene Oxindole Derivatives

J Med Chem. 2018 Oct 25;61(20):9386-9392. doi: 10.1021/acs.jmedchem.8b01137. Epub 2018 Oct 8.

Abstract

3,3'-Spirocyclopentene oxindoles structurally related to Wang's spiropyrrolidine oxindoles have been highlighted as a new class of antiproliferative agents against cancer cell lines with wild-type p53 status (IC50 up to 0.96 μM on SJSA-1 and 2.9 μM in HCT116 p53-wt). Inhibition of the MDM2-p53 interactions has been demonstrated through in vitro HTRF assays (IC50 up to 3.1 nM), while Western blot analysis showed activation of p53 selectively in HCT116 cancer cell lines with wild-type p53.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Drug Design
  • HCT116 Cells
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Oxindoles / chemistry*
  • Oxindoles / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Spiro Compounds / chemistry*
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Oxindoles
  • Spiro Compounds
  • Tumor Suppressor Protein p53
  • 2-oxindole
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2