Novel reduced benzo[j]fluranthen-3-ones from Cladosporium cf. cladosporioides with cytokine production and tyrosine kinase inhibitory properties

J Antibiot (Tokyo). 2001 Jun;54(6):479-88. doi: 10.7164/antibiotics.54.479.

Abstract

A series of reduced benzo[j]fluoranthen-3-ones (1-4) was isolated from fermentations of a fungal strain CBUK20700 (CBS 100220), classified as Cladosporium cf. cladosporioides, during a microbial extract screening programme to identify inhibitors of anti-CD28-induced interleukin-2 (IL-2) production by Jurkat E6-1 cells as potential immunosuppressive agents. These compounds were also found to be tyrosine kinase inhibitors. The structures of compounds 1-4 were elucidated by spectroscopic methods including the HMQC, HMBC and NOESY NMR experiments. The most potent compound in the series, (6bS,7R,8S)-7-methoxy-4,8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (1) inhibited anti-CD28-induced IL-2 production and Abl tyrosine kinase with IC50 values of 400 and 60 nM respectively. The 6b-stereoisomeric 2 was a moderate inhibitor of both IL-2 production and Abl tyrosine kinase while the 8-oxo derivative 3 was inactive in both assays. The 8-O-methyl ether 4 was a moderate inhibitor of IL-2 production but exhibited potent inhibition of Abl tyrosine kinase with an IC50 of 45 nM.

MeSH terms

  • Antibodies / pharmacology
  • CD28 Antigens / immunology
  • Cells, Cultured
  • Cladosporium / chemistry*
  • Cladosporium / classification
  • Cladosporium / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification*
  • Enzyme Inhibitors / pharmacology
  • Fermentation
  • Fluorenes / chemistry
  • Fluorenes / isolation & purification*
  • Fluorenes / pharmacology
  • Humans
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / isolation & purification*
  • Immunosuppressive Agents / pharmacology
  • Inhibitory Concentration 50
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / biosynthesis*
  • Jurkat Cells / drug effects
  • Jurkat Cells / metabolism
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Thailand

Substances

  • Antibodies
  • CD28 Antigens
  • Enzyme Inhibitors
  • Fluorenes
  • Immunosuppressive Agents
  • Interleukin-2
  • XR774
  • fluoranthene
  • Protein-Tyrosine Kinases
  • benzo(k)fluoranthene