N- and C-terminal modifications of negamycin

• Published in: Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (14), p.2413-2418
• Main Authors: Raju, B, Mortell, Kathleen, Anandan, Sampathkumar, O'Dowd, Hardwin, Gao, Hongwu, Gomez, Marcela, Hackbarth, Corinne, Wu, Charlotte, Wang, Wen, Yuan, Zhengyu, White, Richard, Trias, Joaquim, Patel, Dinesh V
• Format: Article
• Language: English
• Subjects: Amino Acids, Diamino - chemistry; Amino Acids, Diamino - pharmacology; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria - drug effects; Bacterial Proteins - biosynthesis; Biological and medical sciences; Drug Design; Escherichia coli - drug effects; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Hydrazines - chemistry; Indicators and Reagents; Medical sciences; Mice; Microbial Sensitivity Tests; Molecular Conformation; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - chemical synthesis; Protein Synthesis Inhibitors - pharmacology; Sepsis - drug therapy; Sepsis - microbiology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00393-7

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 β-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 μM), has antibacterial activity ( Escherichia coli, MIC=16 μg/mL), and is efficacious in an E. coli murine septicemia model (ED 50=16.3 mg/kg). An orthogonally protected β-amino acid derivative was synthesized and used in synthesis of negamycin analogues. The N-terminal modifications have lead to the identification of active analogues, whereas the C-terminal modifications resulted in complete loss of antibacterial activity.