Azaphilones with endothelin receptor binding activity produced by Penicillium sclerotiorum: taxonomy, fermentation, isolation, structure elucidation and biological activity

J Antibiot (Tokyo). 1995 Sep;48(9):913-23. doi: 10.7164/antibiotics.48.913.

Abstract

A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number X11853) active in assays for the detection of antagonists of the endothelin-A (ETA) and endothelin-B (ETB) receptors has been identified. The series includes two novel sclerotiorin analogues, (8S,8 alpha-R)-7-deacetyl-1,O8,8,8a-tetrahydro-7-epi-sclerotiorin, 1, and its 5-dechloro analogue, 2. It also includes 5-chloroisorotiorin, 6, previously unreported as a natural product, in addition to the major product of these fermentations, (+)-sclerotiorin, 5. Data for the inhibition of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding in the ETA and ETB receptor assays respectively are reported for this series. Compounds 1 and 2 were more selective for the rabbit ETA receptor than for the rat ETB receptor. The IC50 values for 1 and 2 were 9 and 28 microM respectively in an assay based on binding of ET-1 to rabbit ETA receptors. In an assay based on the binding of ET-3 to the rat ETB receptor compounds 1 and 2 exhibited IC50's of 77 and 172 microM. Members of this series of compounds demonstrated antagonist behavior in a secondary assay based on blockade of ET-1 stimulated arachidonic acid release from rabbit renal artery smooth muscle cells, when present at concentrations of > or = 30 microM.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzopyrans / chemistry
  • Benzopyrans / isolation & purification*
  • Benzopyrans / pharmacology
  • Cells, Cultured
  • Endothelin Receptor Antagonists*
  • Fermentation
  • Humans
  • Molecular Structure
  • Penicillium
  • Rabbits
  • Rats
  • Receptors, Endothelin / metabolism*
  • Species Specificity
  • Structure-Activity Relationship

Substances

  • 7-deacetyl-5-dechloro-1,O(8),8,8a-tetrahydro-7-epi-sclerotiorin
  • Benzopyrans
  • Endothelin Receptor Antagonists
  • Receptors, Endothelin
  • isochromophilone III