Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorialsynthesis

Citation
Kc. Nicolaou et al., Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorialsynthesis, CHEM-EUR J, 7(17), 2001, pp. 3824-3843
Citations number
65
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry
Journal title
CHEMISTRY-A EUROPEAN JOURNAL
ISSN journal
0947-6539 → ACNP
Volume
7
Issue
17
Year of publication
2001
Pages
3824 - 3843
Database
ISI
SICI code
0947-6539(20010903)7:17<3824:SABEOV>2.0.ZU;2-G
Abstract
Based on the notion that dimerization and/or variation of amino acid 1 of v ancomycin could potentially enhance biological activity, a series of synthe tic and chemical biology studies were undertaken in order to discover poten t antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinator ial synthesis in the presence of vancomycin's target Ac-2-L-Lys-D-Ala-D-Ala ) to generate libraries of vancomycin dimers. Screening of these compound l ibraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistan t and, most significantly, vancomycin-resistant bacteria.