title: Azaphilones with endothelin receptor binding activity produced by Penicillium sclerotiorum: taxonomy, fermentation, isolation, structure elucidation and biological activity.
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.
authors.affiliation: Xenova Ltd, Slough, UK.
authors.forename: L
authors.initials: L
authors.lastname: Pairet
authors.forename: S K
authors.initials: SK
authors.lastname: Wrigley
authors.forename: I
authors.initials: I
authors.lastname: Chetland
authors.forename: E E
authors.initials: EE
authors.lastname: Reynolds
authors.forename: M A
authors.initials: MA
authors.lastname: Hayes
authors.forename: J
authors.initials: J
authors.lastname: Holloway
authors.forename: A M
authors.initials: AM
authors.lastname: Ainsworth
authors.forename: W
authors.initials: W
authors.lastname: Katzer
authors.forename: X M
authors.initials: XM
authors.lastname: Cheng
authors.forename: D J
authors.initials: DJ
authors.lastname: Hupe
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D005285:Fermentation; D006801:Humans; D015394:Molecular Structure; D010407:Penicillium; D011817:Rabbits; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: C096613:7-deacetyl-5-dechloro-1,O(8),8,8a-tetrahydro-7-epi-sclerotiorin; D001578:Benzopyrans; D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; C095345:isochromophilone III