engleski

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

Peptidoglycan monomer (PGM, ß-D-GlcpNAc-(1→4)-D-MurpNAc-L-Ala-D-isoGln-mesoA2pm(eNH2)-D-Ala-D-Ala), the 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-tyrozyl-PGM [2] and (adamant-1-yl)-acetyl-PGM [3] exhibit immunostimulating activity similar to the activity of PGM. 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 adamantyl moiety. 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-glycine. The anhydride was prepared utilizing (a) dicyclohexycarbodiimide and (b) N-ethyl-N’-3-dimethylaminopropylcarbodiimide hydrochloride. The reaction of the PGM with anhydride (a) gave a mixture of two products (A and B) that have different chromatographycal mobilities and the reaction with anhydride (b) resulted in product A only. Products were isolated by gel filtration on Sephadex LH 20 in 60 % ethanol. The structure of the product A was confirmed by mass spectrometry, 1H and 13C NMR, and total acid hydrolysis. Treatment of A with dinitrofluorobenzene, followed by total acid hydrolysis corroborated the existence of peptide bond on e-amino group of diaminopimelic acid. The structure of B is still explored by 1H-NMR, 13C-NMR and mass spectrometry. [1] Tomašić, J., Hanzl-Dujmović, I., Špoljar, B., Vranešić, B., Šantak, M., Jovičić, A. : Vaccine, 18 (2000), 1236-1243. [2] Hršak, I., Ljevaković, Đ., Tomašić, J., Vranešić, B., In Immunotherapy of Infection; Masihi, N., Ed.; Marcel Dekker, Inc.: New York, (1994), 249-257. [3] Ljevaković, Đ., Tomašič, J., Šporec, V., Halassy Špoljar, B., Hanzl-Dujmović, I. : Biorg. Med. Chem., 8 (2000), 2441-2449.

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