Synthese des dansylierten Park-Nucleotids und vereinfachter Analoga der Muraymycin-Antibiotika

Abstract

The conversion of Park's nucleotide to Lipid I in the bacterial cell wall biosynthesis is catalyzed by the enzyme MraY. This enzyme is an interesting target for new antibiotics. In the present thesis a total synthesis of fluorescence mediated Park's nucleotide, for MraY assays, is presented. The synthesis starts with commercial available N-acetylglucosamine and leads in 14 steps in a total yield of 4 % to the desired product. This synthetic route based partially on a published synthesis of Park's nucleotide, where many steps needed to be optimized. New methods for the synthesis of the peptide chain and subsequently coupling with a carbohydrate building block were investigated. As part of this synthetic route uridine diphosphate N-acetylmuramic acid, as a substrate for MurC assays, was prepared in 8 steps starting from protected N-acetylmuramic acid with a total yield of 15 %. The muraymycins, a class of natural nucleoside antibiotics, inhibit MraY efficiently. In this thesis the basis of the synthesis of various simplified muraymycin analogs were laid. The ureapeptide chain was varied to determine the influence on inhibitor activity of this building block. Replacing the complex amino acid epicapreomycidine by the commercial available amino acids L-lysine, L-ornithine, L-arginine, L-alanine and L-methionine simplifies the synthesis of the ureapeptide chain a lot. Furthermore a stereospecific synthesis of protected 2S,3S-diamino hexanoic acid is described herein. This amino acid should replace L-hydroxy leucine, which can be found in natural muraymycins often esterified with a fatty acid. This should lead to more stable muraymycin analogs with an amide bond replacing the ester bond. Recently the L-lysine containing ureapeptide, described in this thesis, was used to synthesize different muraymycin derivatives. The inhibitor activities of these compounds were determined by a fluorescence based MraY assay. A big amount of diverse potential inhibitors could be obtained per combination of different, in this thesis synthesized ureapeptides and amino acids with various uridine derivatives.