Asterric acid, a new endothelin binding inhibitor.

Abstract

Endothelin (ET) is a potent vasoconstrictor/ pressor peptide consisting of 21 amino acid residues isolated from the cultures of porcine aortic endothelial cells1}. Analysis of a human genomic library reveals three forms of ET (ET-1, ET-2 and ET-3) which have more than 70% homology with one another2). In various organs, high affinity and specific receptors for ET have been found3). They have been distinguished as receptors ETA and ETB4-5). ET-1 exhibits potent and long-lasting vasoconstrictive activity in vivo and in vitro1"1, as a result of binding to the ETAreceptor. In the course of our screening program for ET-1 binding inhibitors from microorganisms, we isolated asterric acid (Fig. 1, 1) as an active substance from the culture filtrate of a fungus, Aspergillus sp. Asterric acid had been reported as a metabolite of a fungus6'7). We have shown that it has the property of inhibiting ET-1 binding to the ETA receptor of A10 cells8).The fungus was cultivated on a rotary shaker at 25°C for 7 days in 500-ml Erlenmeyer flasks each containing 100ml ofKl5 medium which consists of 2% malt extract, 2% glucose, 0.1% peptone and 0.1% agar.

A New Diphenyl Ether from Marine-derived Fungus Aspergillus sp. B-F-2

“…[2], and etc. Their reported bioactivities mainly focus on the endothelin (ET) binding inhibitory activities [1,8], with nearly no reports on cytotoxicity. Our study demonstrated for the first time that compound having diphenyl ether skeleton showed S phase inhibitory activity against K562 cell line.…”

“…Asterric acid, possessing a diphenyl ether structure, was the first non-peptide endothelin (ET) binding inhibitor discovered [1,2]. In this paper we mainly report the isolation and structure determination of the new diphenyl ether (1), and its preliminary in vitro cytotoxicity against the K562 cell line.…”

“…Bioassay-guided isolation led to one new asterric acid derivative dimethyl 2,3Ј-dimethoxyosoate (1), and three known fungal metabolites monomethylsulochrin (2), emodin (3), and questin (4) (Fig. 1).Asterric acid, possessing a diphenyl ether structure, was the first non-peptide endothelin (ET) binding inhibitor discovered [1,2]. In this paper we mainly report the isolation and structure determination of the new diphenyl ether (1), and its preliminary in vitro cytotoxicity against the K562 cell line.…”

Bioactive Asterric Acid Derivatives from the Antarctic Ascomycete Fungus Geomyces sp.

“…1 It is also an inhibitor of vascular endothelial growth factor (VEGF) and an endothelin receptor antagonist for the treatment of early stage idiopathic pulmonary fibrosis. 2,3 Although a number of asterric acid derivatives have been claimed to be useful in the treatment of myocardial infarction and renal insufficiency, 4 none of them has been reported to display antifungal activity.…”

3′-Demethyldihydromaldoxin and dihydromaldoxin, two anti-inflammtory diaryl ethers from a Steganospora species

“…[4][5][6] Asterric acid has been described to be the first non-peptidic inhibitor of the endothelin receptor and dechlorodihydromaldoxin and dihydromaldoxin were found to selectively inhibit endothelin-1 binding to endothelin type A receptor with IC 50 values of 1.5 and 20 mM, respectively. 7,8 These compounds also inhibit the increase in intracellular Ca 2 þ concentration elicited by 1 nM endothelin-1 in A10 cells. 8 In addition, the asterric acid derivatives methyl asterric acid, methyl 3-chloroasterric acid and methyl 3,5-dichloroasterric acid exerted inhibitory activity on VEGF-induced capillary-like tube formation of human umbilical vein endothelial cells in vitro.…”