Synthesis of novel adamantylacetyl derivative of peptidoglycan monomer - Biological evaluation of immunomodulatory peptidoglycan monomer and respective derivatives with lipophilic substituents on amino group

Novel synthetic analogue of immunomodulatory peptidoglycan monomer 1 (PGM), (adamant-1-yl)-CH2CO-PGM (2), was prepared by acylation of epsilon-amino g roup of diaminopimelic acid with symmetrical (adamant-1-yl)-acetic acid anh ydride in the presence of triethylamine. The product was isolated by gel fi ltration on Sephadex G-25, followed by ion exchange chromatography on SP-Se phadex C-25. The susceptibility of (adamant-l-yi)-CH2CO-PGM to hydrolysis w ith N-acetylmuramyl-L-alanine amidase was demonstrated, and the product of hydrolysis, (adamant-1-yl)-CH2CO-pentapeptide 3, was characterized. Both 2 and 3 are water soluble and non-pyrogenic compounds. Immunomodulatory activ ity of PGM (adamant-1-yl)-CH2CO-PGM and structurally related derivative Boc -Tyr-PGM was compared in experiments in vivo, in mice, using ovalbumin (OVA ) as an antigen. All three tested compounds exhibited comparable immunostim ulating effects with respect to the induction of anti-ovalbumin immunoglobu lin G. The results of evaluation of biological activity show that the subst itution of free amino group in the parent peptidoglycan molecule with bulky lipophilic substituents did not affect the susceptibility to hydrolysis wi th N-acetylmuramyl-L-alanine amidase and did not alter markedly the immunos timulating activity. The results also indicate that the free amino group in the peptide chain is not a necessary requirement in the mechanism of immun ostimulation of tested immunomodulators. (C) 2000 Elsevier Science Ltd. All rights reserved.