Design, synthesis, and molecular modeling of coumarin derivatives as MDM2 inhibitors targeting breast cancer

Chem Biol Drug Des. 2022 Apr;99(4):609-619. doi: 10.1111/cbdd.14028. Epub 2022 Feb 22.

Abstract

The coumarin ring was used as a central scaffold that was substituted with a variety of bioactive functional groups, for designing and synthesizing novel MDM2 inhibitors targeting breast cancer. The synthesized derivatives, 3c, 3d, 3g, 7b, 7c and 8 with IC50s ranging from 9.4 to 9.9 µM were evaluated for their safety on MCF10a normal breast cell line. The compounds showed selectivity indices of 2.15, 3.85, 2.75, 1.38, 3.72 and 5.20 respectively. 7c was selected for further investigation, the compound was capable of down-regulating MDM2 and the anti-apoptosis proteins Bcl-2 and Bcl-xL, up-regulating the level of p53 and the pro-apoptosis protein BAX, causing cell cycle arrest at G2/M phase and activating Caspase-9 to induce apoptosis. Molecular docking study revealed the capability of derivative 7c to interact with the key amino acids in p53 binding pocket of MDM2 protein. Moreover, the physicochemical properties of compound 7c were studied in silico.

Keywords: MDM2; apoptosis; breast cancer; coumarin; molecular docking.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Apoptosis
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Coumarins / pharmacology
  • Coumarins / therapeutic use
  • Female
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Coumarins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2