Rare Streptomyces sp. polyketides as modulators of K-Ras localisation

Org Biomol Chem. 2014 Jul 21;12(27):4872-8. doi: 10.1039/c4ob00745j.


Chemical investigations of a soil-derived Streptomyces sp. led to the isolation of five new polyketides, (+)-oxanthromicin, (±)-hemi-oxanthromicins A/B, (±)-spiro-oxanthromicin A and oxanthroquinone, and the known alkaloid staurosporine, and the detection of four new metastable analogues, (±)-spiro-oxanthromicins B1/B2/C1/C2. Among the compounds tested, SAR investigations established that the synthetic oxanthroquinone ethyl ester and 3-O-methyl-oxanthroquinone ethyl ester were optimal at mislocalising oncogenic mutant K-Ras from the plasma membrane of intact Madin-Darby canine kidney (MDCK) cells (IC50 4.6 and 1.2 μM), while a sub-EC50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC50 60 pM). These studies demonstrate that a rare class of Streptomyces polyketide modulates K-Ras plasma membrane localisation, with implications for the future treatment of K-Ras dependent cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / chemistry
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Dogs
  • Humans
  • Magnetic Resonance Spectroscopy
  • Polyketides / chemistry
  • Polyketides / pharmacology*
  • Proto-Oncogene Proteins / analysis*
  • Proto-Oncogene Proteins p21(ras)
  • Streptomyces / metabolism*
  • Structure-Activity Relationship
  • ras Proteins / analysis*


  • KRAS protein, human
  • Polyketides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins