title: Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues.
abstract: The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively nonpolar substituents approach or match the chloro-substituted vancomycin and were insensitive to the electronic character of the substituent (e.g., Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Pinchman
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D001895:Boron / Q000737:chemistry; D002712:Chlorides; D013293:Enterococcus faecalis / Q000187:drug effects; D007202:Indicators and Reagents; D008024:Ligands; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020713:Vancomycin Resistance / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002712:Chlorides; D007202:Indicators and Reagents; D008024:Ligands; C079913:VanB protein, Enterococcus; D014640:Vancomycin; D001895:Boron