engleski

Preparation of novel amphiphilic desmuramyl peptide derivatives

Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D- isoglutamine, MDP) is the smallest structural unit of peptidoglycans showing immunostimulating activity. MDP analogues without the hydrophilic N- acetylmuramyl moiety are called desmuramyl peptides (DMP) and are an important class of compounds used for the development of adjuvants.1 Structure-activity studies (SAR) of MDPs and DMPs suggest that the introduction of lipophilic substituent (e.g. adamantyl, aryl, dodecyl) into dipeptide core can increase its adjuvant activity.1, 2 Furthermore, experiments in vivo showed that mannosylation of the adamantylated DMPs amplified their adjuvant activity.3 Mannose unit was attached to DMPs because it may contribute to their recognition by specific mannose receptors expressed at immune cells.1 This work is a continuation of our ongoing SAR study of DMP analogues. We designed and prepared novel lipophilic DMPs where lipophilic subunits (adamantyl, adamantyl triazolyl, dodecyl) were introduced at the D-isoGln side chain. Adamantyl subunit was incorporated into DMP structure through 1, 2, 3-triazole ring obtained via CuAAC reaction and subsequent amidation. Three different amidation methods were investigated for incorporation of each subunit. DMP with adamantyl moiety was also prepared in a completely different route starting from the Boc protected D-isoGln. The final aim of the synthetic part of this work is to prepare amphiphilic DMPs (Fig. 1) where mannose unit will be introduced through glycolyl linker on the N-terminus of all prepared lipophilic DMPs.

immunostimulating activity, muramyl dipeptide, peptide synthesis

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