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

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...

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Bibliographic Details
Published in:	Journal of antibiotics Vol. 48; no. 9; p. 913
Main Authors:	Pairet, L, Wrigley, S K, Chetland, I, Reynolds, E E, Hayes, M A, Holloway, J, Ainsworth, A M, Katzer, W, Cheng, X M, Hupe, D J
Format:	Journal Article
Language:	English
Published:	Japan 1995
Subjects:	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
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Summary:	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.
ISSN:	0021-8820
DOI:	10.7164/antibiotics.48.913