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Publication 23  

  1. Solid- and Solution-Phase Synthesis of Vancomycin and Vancomycin Analogues with Activity against Vancomycin-Resistant Bacteria
    K. C. Nicolaou, S. Y. Cho, R. Hughes, N. Winssinger, C. Smethurst, H. Labischinski, R. Endermann
    Chem. Eur. J. 2001, 7, 3798-3823

The development of a new synthetic technology based on the design of a novel selenium safety catch linker is described for the solid-phase semisynthesis of monomeric vancomycin (see for example 1, R1 = tert-butyldimethylsilyl, R2 = protected carbohydrates), along with the solid- and solution-phase synthesis of vancomycin libraries, which were further tested for their biological activity.

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.

DOI: 10.1002/1521-3765(20010903)7:17<3798::AID-CHEM3798>3.0.CO;2-6 

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