Design and synthesis of simple macrocycles active against vancomycin-resistant Enterococci (VRE)

16-Membered meta,para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) were designed and synthesized. The structural key features of these biaryl ether contg. macrocycles are (1) the presence of beta -amino-alpha -hydroxy acid or alpha ,beta -diamino acid as the C-terminal component of the cyclopeptide, and (2) the presence of a hydrophobic chain or lipidated aminoglucose at the appropriate position. Cycloetherification by an intramol. nucleophilic arom. substitution reaction (SNAr) is used as the key step for the construction of the macrocycle. The atropselectivity of this ring-closure reaction is found to be sensitive to the peptide backbone and chemoselective cyclization (phenol vs. primary amine) is achievable. Glycosylation of phenol was realized with freshly prepd. 3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-deoxy-alpha -D-glucopyranosyl bromide under phase-transfer conditions. Min. inhibitory concns. for all of the derivs. are measured by using a std. microdilution assay, and potent bioactivities against both sensitive and resistant strains are found for some of these compds. [MIC (min. inhibitory concn.) = 4 micro g mL-1 against VRE]. From these preliminary SAR studies, it was anticipated that both the presence of a hydrophobic substituent and an appropriate structure of the macrocycle were required for this series of compds. to be active against VRE. [on SciFinder (R)]


Published in:
Chemistry--A European Journal, 12, 20, 5334-5351
Year:
2006
Keywords:
Note:
CAN 145:336305
34-3
Amino Acids, Peptides, and Proteins
Institut de Chimie des Substances Naturelles,CNRS,Gif-sur-Yvette,Fr.
Journal
0947-6539
written in English.
1404-90-6 (Vancomycin); 61036-62-2 (Teicoplanin); 103060-53-3 (Daptomycin); 126602-89-9 (Synercid) Role: PAC (Pharmacological activity), BIOL (Biological study) (prepn. of biaryl ether-contg. glycosylated macrocycles, and their antibacterial activity against vancomycin-resistant Enterococci (VRE); 868749-38-6P; 868749-40-0P; 868749-93-3P; 868749-94-4P; 909805-98-7P; 909896-26-0P; 909896-27-1P; 909896-28-2P; 909896-29-3P; 909896-30-6P; 909896-32-8P; 909896-33-9P; 909896-34-0P; 909896-36-2P; 909896-37-3P; 909896-38-4P; 909896-40-8P; 909902-62-1P; 909902-63-2P; 909902-64-3P; 909902-65-4P; 909902-66-5P; 909902-67-6P; 909902-68-7P; 909902-69-8P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. of biaryl ether-contg. glycosylated macrocycles, and their antibacterial activity against vancomycin-resistant Enterococci (VRE); 112-16-3 (Lauroyl chloride); 350-46-9 (1-Fluoro-4-nitrobenzene); 2577-90-4; 3303-84-2 (3-(tert-Butoxycarbonylamino)propanoic acid); 6404-29-1 (6-(tert-Butoxycarbonylamino)caproic acid); 14131-62-5; 16937-99-8; 173775-54-7; 850404-73-8; 868684-96-2; 868685-01-2; 909805-89-6 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. of biaryl ether-contg. glycosylated macrocycles, and their antibacterial activity against vancomycin-resistant Enterococci (VRE); 353271-70-2P; 847505-78-6P; 868684-97-3P; 868684-98-4P; 868684-99-5P; 868749-27-3P; 868749-28-4P; 868749-29-5P; 868749-30-8P; 868749-31-9P; 868749-32-0P; 868827-19-4P; 909805-88-5P; 909805-90-9P; 909805-91-0P; 909805-92-1P; 909805-93-2P; 909805-95-4P; 909805-96-5P; 909805-99-8P; 909896-02-2P; 909896-03-3P; 909896-04-4P; 909896-06-6P; 909896-07-7P; 909896-08-8P; 909896-09-9P; 909896-10-2P; 909896-11-3P; 909896-12-4P; 909896-13-5P; 909896-14-6P; 909896-15-7P; 909896-17-9P; 909896-41-9P; 909902-55-2P; 909902-56-3P; 909902-58-5P; 909902-70-1P; 1002752-06-8P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. of biaryl ether-contg. glycosylated macrocycles, and their antibacterial activity against vancomycin-resistant Enterococci (VRE); 868749-33-1P; 868749-34-2P; 868749-49-9P; 868749-50-2P; 909896-16-8P; 909896-18-0P; 909896-19-1P; 909896-20-4P; 909896-21-5P; 909896-22-6P; 909896-23-7P; 909896-24-8P; 909896-25-9P; 909896-31-7P; 909902-57-4P; 909902-59-6P; 909902-60-9P; 909902-61-0P Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. of biaryl ether-contg. glycosylated macrocycles, and their antibacterial activity against vancomycin-resistant Enterococci (VRE)
Laboratories:




 Record created 2010-11-25, last modified 2018-01-28


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