Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid.
The synthesis and biological evaluation of a series of vancomycin aglycon analogues bearing alternative residue 1 N-methyl-D-amino acids are described. The analogues were prepared to define whether H-bonding d-amino acids could improve the affinity for the model ligands N,N'-Ac(2)-L-Lys-D-Ala-D-Ala (2) and N,N'-Ac(2)-L-Lys-D-Ala-D-Lac (3) and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophiles (hydrazines and amines) on the residue 1 D-amino acids are described that were examined for their ability to react with the C-terminal ester of 3, forming a covalent attachment of L-Lys-D-Ala to the natural product analogues.
Crane
Christine M
CM
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Boger
Dale L
DL
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D007930:Leucine / Q000737:chemistry*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020713:Vancomycin Resistance
D000588:Amines; D000900:Anti-Bacterial Agents; D006834:Hydrazines; D008024:Ligands; D014640:Vancomycin; D007930:Leucine