Azaphilones with Endothelin Receptor Binding Activity Produced by Penicillium sclerotiorum: Taxonomy, Fermentation, Isolation, Structure Elucidation and Biological Activity

• Published in: Journal of antibiotics Vol. 48; no. 9; pp. 913 - 923
• 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., CHARLTON, P., DOHERTY, A. M.
• Format: Journal Article
• Language: English
• Published: TOKYO JAPAN ANTIBIOTICS RESEARCH ASSOCIATION 1995; JAPAN ANTIBIOT RES ASSN; Japan Antibiotics Research Association
• Subjects: Animals; Benzopyrans - chemistry; Benzopyrans - isolation & purification; Benzopyrans - pharmacology; Biological and medical sciences; Biotechnology & Applied Microbiology; Cells, Cultured; Endothelin Receptor Antagonists; Fermentation; General pharmacology; Humans; Immunology; Life Sciences & Biomedicine; Medical sciences; Microbiology; Miscellaneous; Molecular Structure; Penicillium; Penicillium sclerotiorum; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rabbits; Rats; Receptors, Endothelin - metabolism; Science & Technology; Species Specificity; Structure-Activity Relationship; DESIGN; ET(A); ANTAGONIST; ETA; ACID; CLONING; POTENCY; TALAROMYCES-LUTEUS; CDNA; EXPRESSION; Endothelin; Ligand; Penicillium; Taxonomy; Peptide hormone; Chemical structure; Fermentation; Biological activity; Fungi; Microbial origin; Peptidergic receptor; Vasoconstrictor agent; Isolation; Fungi Imperfecti; Thallophyta
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.48.913

A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number XI1853) 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, 8a-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 μM 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 μM. 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 ≥30μM.