title: N- and C-terminal modifications of negamycin.
abstract: Negamycin 1 is a bactericidal antibiotic with activity against Gram-negative bacteria, and served as a template in an antibiotic discovery program. An orthogonally protected beta-amino acid derivative 3a was synthesized and used in parallel synthesis of negamycin derivatives on solid support. This advanced intermediate was also used for N- and C-terminal modifications using solution-phase methodologies. The N-terminal modifications have resulted in the identification of active analogues, whereas the C-terminal modifications resulted in complete loss of antibacterial activity. The N-methyl negamycin analogue, 19a, inhibits protein synthesis (IC(50)=2.3 microM), has antibacterial activity (Escherichia coli, MIC=16 microgram/mL), and is efficacious in an E. coli murine septicemia model (ED(50)=16.3mg/kg).
authors.affiliation: Versicor Inc., 34790 Ardentech Court, CA 94555, Fremont, USA. raju@versicor.com
authors.forename: B
authors.initials: B
authors.lastname: Raju
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mortell
authors.forename: Sampathkumar
authors.initials: S
authors.lastname: Anandan
authors.forename: Hardwin
authors.initials: H
authors.lastname: O'Dowd
authors.forename: Hongwu
authors.initials: H
authors.lastname: Gao
authors.forename: Marcela
authors.initials: M
authors.lastname: Gomez
authors.forename: Corinne
authors.initials: C
authors.lastname: Hackbarth
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wu
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Richard
authors.initials: R
authors.lastname: White
authors.forename: Joaquim
authors.initials: J
authors.lastname: Trias
authors.forename: Dinesh V
authors.initials: DV
authors.lastname: Patel
mesh_terms: D000599:Amino Acids, Diamino / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins / Q000096:biosynthesis; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006834:Hydrazines / Q000737:chemistry; D007202:Indicators and Reagents; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000599:Amino Acids, Diamino; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006834:Hydrazines; D007202:Indicators and Reagents; D011500:Protein Synthesis Inhibitors; C100200:negamycin