N'-(alpha-aminoacyl)- and N'-alpha-(N(alpha)-alkylamino)acyl derivatives of vancomycin and eremomycin. I. Synthesis of N'-(alpha-aminoacyl)- and N'-alpha-(N(alpha)-alkylamino)acyl derivatives of vancomycin and eremomycin by selective aminoacylation of the amino sugar of the disaccharide branch.
The acylation of unprotected vancomycin or eremomycin with activated esters of N(alpha)-protected amino acids or N(alpha)-alkyl-N(alpha)-Fmoc-amino acids is directed selectively to the amino group of the disaccharide branch (N') and after Fmoc-group removal leads to the corresponding N'-alpha-aminoacyl derivatives. A series of N'-alpha-aminoacyl and N'-alpha-(N(alpha)-alkylamino)acyl derivatives of eremomycin and vancomycin containing hydrophobic moieties has been synthesized. The structures of all derivatives were confirmed by Electrospray Ionization mass-spectral (ESI MS) analysis, and by chemical degradation methods. Position of the introduced N'-alpha-aminoacyl- and N-(N(alpha)-alkylamino)acyl groups were determined after Edman degradation and acidic hydrolysis. The structures of the synthesized starting reagents (N(alpha)-alkylamino acids or N(alpha)-alkyl-N(alpha)-Fmocamino acids) were confirmed by NMR-spectra data. In general, N'-(N-alkylglycyl)-derivatives were more active than the corresponding N'-alpha-(N(alpha)-alkylamino)acylated derivatives containing other amino acids (L-Lys, L-Met, L-Orn, L- and D-Ala, L- and D-Phe and benzyl-O-L-Tyr).
Preobrazhenskaya
Maria N
MN
Gause Institute of New Antibiotics, Moscow, Russia. mnp@space.ru
Olsufyeva
Evgenia N
EN
Miroshnikova
Olga V
OV
Plattner
Jake J
JJ
Chu
Daniel
D
Printsevskaya
Svetlana S
SS
D049148:Aminoacylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D006020:Glycopeptides / Q000138:chemical synthesis*; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; C053759:eremomycin; D014640:Vancomycin