Synthesis and siderophore activity of albomycin-like peptides derived from N5-acetyl-N5-hydroxy-L-ornithine

• Published in: Journal of medicinal chemistry Vol. 34; no. 3; pp. 956 - 968
• Main Authors: Dolence, E. Kurt, Lin, Chia En, Miller, Marvin J, Payne, Shelley M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.03.1991
• Subjects: Anti-Bacterial Agents - chemistry; Chemical Phenomena; Chemistry; Escherichia coli - drug effects; Escherichia coli - genetics; Exact sciences and technology; Ferrichrome - analogs & derivatives; Ferrichrome - chemistry; Iron - metabolism; Iron Chelating Agents - chemical synthesis; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacology; Magnetic Resonance Spectroscopy; Molecular Structure; Organic chemistry; Ornithine - analogs & derivatives; Ornithine - chemical synthesis; Ornithine - chemistry; Ornithine - pharmacology; Peptides; Preparations and properties; Quinolines; Shigella flexneri - drug effects; Shigella flexneri - growth & development; Siderophores; Peptides; Siderophore; Biological activity; Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00107a013

N5-Acetyl-N5-hydroxy-L-ornithine (1), the key constituent of several microbial siderophores, has been synthesized in 23% yield overall from N-Cbz-L-glutamic acid 1-tert-butyl ester (6) derived from L-glutamic acid. Reduction of 6 to 7 and treatment with N-[(trichloroethoxy)carbonyl]-O-benzylhydroxylamine (8), and diethyl azodicarboxylate and triphenylphosphine followed by deprotection produced the protected N5-acetyl-N5-hydroxy-L-ornithine derivatives 11 and 12 in large quantities (10-20 g). Following alpha-amino and alpha-carboxyl deprotections of 11 and 12, EEDQ [2-ethoxy-N-(ethoxycarbonyl)-1,2-dihydroquinoline] mediated peptide coupling and final deprotection provided amino acid 1 and six albomycin-like peptides (20, 23, 25, 28, 35, and 36). The growth-promoting ability of each was evaluated with the siderophore biosynthesis mutant Shigella flexneri SA240 (SA 100 iucD:Tn5). These results indicate that substantial modification of the framework of peptide-based siderophores can be tolerated by microbial iron-transport systems.