Chemistry and biology of moverastins, inhibitors of cancer cell migration, produced by Aspergillus

Chem Biol. 2005 Dec;12(12):1337-47. doi: 10.1016/j.chembiol.2005.09.017.

Abstract

Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Antineoplastic Agents / pharmacology*
  • Aspergillus / chemistry*
  • Benzaldehydes / chemistry*
  • Benzaldehydes / pharmacology*
  • Cell Line, Tumor
  • Cell Membrane / chemistry
  • Cell Movement / drug effects*
  • Cyclohexanones / chemistry*
  • Cyclohexanones / pharmacology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Signal Transduction / drug effects
  • Stereoisomerism
  • ras Proteins / analysis
  • ras Proteins / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Benzaldehydes
  • Cyclohexanones
  • moverastin A
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • ras Proteins