N′-(α-Aminoacyl)- and N′-α-(Nα-Alkylamino)acyl Derivatives of Vancomycin and Eremomycin

Abstract

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).