Biological screening of cucurbitacin inspired estrone analogs targeting mitogen-activated protein kinase (MAPK) pathway

Chem Biol Drug Des. 2017 Sep;90(3):478-484. doi: 10.1111/cbdd.12963. Epub 2017 Apr 25.

Abstract

Assembly of cucurbitacin inspired estrone analogs has been previously synthesized and screened against melanoma cell lines. Further synthetic optimization was executed via installation of Azide polar functional moiety across 23, 24 α, β-unsaturated ketone side chain using Michael addition reaction. This was followed by biological screening against melanoma cell lines employing MTT assay, in-cell-based ELISA assay, and Western blot analysis to monitor the potential of the synthesized analogs to inhibit the phosphorylated ERK levels. This resulted in evolution of MH-4 possessing IC50 of 3.59 μm with significant decrease in the p-ERK and targeting MAPK pathway.

Keywords: MAPK pathway; Michael addition; cucurbitacins; estrone; melanoma.

Publication types

  • Letter

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cucurbitacins / chemistry
  • Cucurbitacins / metabolism
  • Cucurbitacins / toxicity*
  • Enzyme-Linked Immunosorbent Assay
  • Estrone / analogs & derivatives
  • Estrone / metabolism
  • Estrone / toxicity*
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinase 1 / analysis
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / analysis
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins B-raf / chemistry
  • Proto-Oncogene Proteins B-raf / metabolism

Substances

  • Estrone
  • Cucurbitacins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3