Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between D-Ala-D-Lac binding and hydrophobic effect

A modified vancomycin binding pocket (D-O-E ring) incorporating a CHNHCOR function at the AA4 position is designed and synthesized. Potent bioactivities against both sensitive- and resistant-strain are found for some of these compds. (MIC 4 micro g/mL against VREF). From this preliminary SAR studies, it was speculated that the D-Ala-D-Ala binding was required for this series of compds. since the corresponding des-leucine deriv. is inactive. The presence of long aliph. chain was important for the desired activities and such hydrophobic effect is specific as no beneficial effect is obsd. when the same aliph. chain was attached to the other part of the mol. [on SciFinder (R)]


Published in:
Bioorganic & Medicinal Chemistry Letters, 15, 3, 743-746
Year:
2005
Keywords:
Chirality (axial; synthesis of macrocyclic glycopeptides with axial chirality via thermal atropoisomerization); Structure-activity relationship (bactericidal; synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Etherification (cyclo; synthesis by glycosylation of parent 16-membered biaryl ether and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Reduction; Substitution reaction (synthesis by azide redn. followed by SNAr-based macrocyclization via biaryl ethers and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Glycosylation (synthesis by glycosylation of parent 16-membered biaryl ether and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Antibiotics; Staphylococcus aureus (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Heterocyclic compounds; Macrocyclic compounds Role: PAC (Pharmacological activity) ; RCT (Reactant) ; SPN (Synthetic preparation) ; BIOL (Biological study) ; PREP (Preparation) ; RACT (Reactant or reagent) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Glycopeptides Role: PAC (Pharmacological activity) ; SPN (Synthetic preparation) ; BIOL (Biological study) ; PREP (Preparation) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); Isomerization (thermal ; thermal atropoisomerization; synthesis of macrocyclic glycopeptides with axial chirality via thermal atropoisomerization) ; macrocyclic glycopeptide synthesis antibiotic vancomycin resistant enterococci; vancomycin glycopeptide structure activity antibiotic axial chirality; azide redn cycloetherification nucleophilic substitution thermal atropoisomerization glycosylation
Note:
CAN 142:298321
34-3
Amino Acids, Peptides, and Proteins
Institut de Chimie des Substances Naturelles, CNRS,Gif-sur-Yvette,Fr.
Journal
0960-894X
written in English.
847505-77-5P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (synthesis by azide redn. followed by SNAr-based macrocyclization via biaryl ethers and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); 847599-46-6P Role: PAC (Pharmacological activity), RCT (Reactant), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation), RACT (Reactant or reagent) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); 847505-79-7P; 847599-40-0P; 847599-42-2P; 847599-43-3P; 847599-47-7P; 847599-48-8P; 847599-49-9P; 847599-62-6P; 847599-63-7P; 847599-71-7P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); 143-07-7 (n-Dodecanoic acid) Role: RCT (Reactant), RACT (Reactant or reagent) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); 847505-78-6P; 847599-37-5P; 847599-38-6P; 847599-39-7P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of macrocyclic glycopeptides); 1404-90-6DP (Vancomycin) Role: PAC (Pharmacological activity), RCT (Reactant), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation), RACT (Reactant or reagent) (synthesis via SNAr-based macrocyclization and glycosylation and structure-activity relationship against vancomycin-resistant enterococci of vancomycin-type macrocyclic glycopeptides)
Laboratories:




 Record created 2010-11-25, last modified 2018-09-13


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