N- and C-terminal modifications of negamycin

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.