The Hybrid Pyrroloisoindolone-Dehydropyrrolizine Alkaloid (-)-Chlorizidine A Targets Proteins within the Glycolytic Pathway

Chembiochem. 2015 Sep 21;16(14):2002-6. doi: 10.1002/cbic.201500229. Epub 2015 Aug 12.

Abstract

The cytotoxic activity of (-)-chlorizidine A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (-)-chlorizidine A.

Keywords: drug discovery; enolase; glycolysis; mode of action; natural products.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Drug Discovery
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
  • Glycolysis / drug effects*
  • HCT116 Cells
  • Humans
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / pharmacology*
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Phosphopyruvate Hydratase / chemistry
  • Phosphopyruvate Hydratase / metabolism*
  • Proteins / chemistry
  • Proteins / metabolism
  • Streptomyces / chemistry
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Biological Products
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Indole Alkaloids
  • Proteins
  • Tumor Suppressor Proteins
  • chlorizidine
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • ENO1 protein, human
  • Phosphopyruvate Hydratase