Pyrazino[1,2-a]indole-1,4-diones, simple analogues of gliotoxin, as selective inhibitors of geranylgeranyltransferase I

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 21; pp. 3661 - 3663
• Main Authors: VIGUSHIN, David M, BROOKE, Greg, WILLOWS, David, COOMBES, R. Charles, MOODY, Christopher J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 03.11.2003
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Antineoplastic agents; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase; General aspects; Genes, ras - genetics; Gliotoxin - analogs & derivatives; Gliotoxin - pharmacology; Indoles - chemical synthesis; Indoles - pharmacology; Medical sciences; Pharmacology. Drug treatments; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Recombinant Proteins - chemical synthesis; Recombinant Proteins - pharmacology; Structure-Activity Relationship; Antineoplastic agent; Geranylgeranyl-diphosphate geranylgeranyltransferase; Enzyme; Angular nitrogen heterocycle; Transferases; Lactam; Enzyme inhibitor; Selectivity; Tricyclic compound; In vitro; Organic disulfide; Structure activity relation; Analog; Aromatic compound; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.08.022

Some pyrazino[1,2-a]indole-1,4-diones, structurally simplified analogues of the natural mycotoxin gliotoxin, have been synthesised and investigated as inhibitors of prenyltransferases; one compound, 3-acetylthio-9-methoxy-2-methyl-2,3-dihydropyrazino[1,2-a]indole-1,4-dione 10 shows slightly greater selectivity (8-fold) for geranylgeranyltransferase type I (GGTase I) than gliotoxin itself.