N- and C-terminal modifications of negamycin |
| |
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 |
| |
Institution: | Versicor Inc., 34790 Ardentech Court, CA 94555, Fremont, USA. raju@versicor.com |
| |
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). |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|