engleski

Synthesis and biological activity of N-(tert-butyloxycarbonyl)-(adamant-2-yl)-D, L-glycyl-peptidoglycan monomer

Peptidoglycan monomer (PGM, GlcpNAc-MurpNAc-L-Ala-D-isoGln-L-meso-A2pm(eNH2)-D-Ala-D-Ala, PLIVA), disaccharide pentapeptide, is the basic repeating unit of Brevibacterium divaricatum cell wall peptidoglycan. It exhibits, inter alia, strong immunomodulating activity [1]. Semisynthetic derivatives of peptidoglycan monomer, N-tert-butyloxycarbonyl-L-tyrosyl-PGM and (adamant-1-yl)-acetyl-PGM are good substrates [2] for N-acetylmuramyl-L-alanine amidase present in mammalian blood. Neither of them affected [2] the immunostimulating properties of the parent compound. The aim of this work was to prepare the new derivative of PGM containing (N-tert-butyloxycarbonyl)-(adamant-2-yl)-D, L-glycyl-residue and to investigate the structure-activity relationship. It might be expected that even small structural changes can alter the biological activity of the parent compound. Derivatives of PGM containing the adamantyl residue might combine immunostimulating activity of PGM with antiviral activity of the moiety comprising adamantyl residue. The novel adamantylacyl derivative of PGM was prepared by acylation of e-amino group of diaminopimelic acid with symmetrical anhydride of N-(tert-butyloxycarbonyl)-(adamant-2-yl)-D, L-glycyne. The anhydride was prepared utilizing (a) DCC and (b) EDC. The reaction of the PGM with anhydride (a) gave a mixture of two products N-(tert-butyloxycarbonyl)-D, L-(adamantan-2-yl)-glycyl-peptidoglycan monomer (product A) and [N-(tert-butyloxycarbonyl)-D, L-(adamantan-2-yl)-glycyl]2-peptidoglycan monomer (product B) that have different chromatographical mobilities. The reaction with anhydride (b) resulted in product A only. Products were isolated by gel filtration on Sephadex LH 20 and their structures were confirmed. Activity in relation to the structure of the product A was examined in the two different models: in vitro (the susceptibility of A to the N-acetylmuramyl-L-alanine amidase) and in vivo (immunomodulating activity was tested in an experimental model in mice, using ovalbumin as antigen [1]). Product A was a good substrate for N-acetylmuramyl-L-alanine amidase which cleaves it, yielding the disaccharide and the respective peptide. Immunostimulating activity of product A was compared with the activity of PGM and (adamant-1-yl)-acetyl-PGM. Product A didn't exhibit immunostimulating effect in applied experimental model.

PGM; (N-tert-butyloxycarbonyl)-(adamant-2-yl)-D; L-glycyl-residue

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