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N-Acetylmuramyl-L-alanyl-D-isoglutamine α-phenylglycoside was synthesized from α-phenyl-D-glucosaminide peracetate, which was obtained by fusing β-D-glucosamine pentaacetate with phenol and zinc chloride followed by deacetylation. α-Phenyl-N-acetylglucosaminide was converted in two steps into 4,6-O-isopropylidene-N-acetyl-D-muramic acid α-phenylglycoside, which was condensed with L-Ala-D-iGln benzyl ether using the activated ester method. Sequential removal of glycopeptide protecting groups via acid hydrolysis and catalytic hydrogenolysis gave the target product.

N-Acetylmuramyl-L-alanyl-D-isoglutamine α-cyclooctyl- and α-cyclopentadecylglycosides were synthesized. The starting peracetylated α-N-glucosaminides were synthesized by reacting the cycloalkanols with peracetyl α-D-glucosaminyl chloride in the presence of Hg(II) iodide in CH3NO2 with heating or by using ZnCl2/tetrabutylammonium bromide in CH2Cl2 at room temperature. Sequential deacetylation, isopropyl protection, and alkylation by (S)-2-bromopropanoic acid gave α-cycloalkyl-4,6-O-isopropylidene-N-acetyl-D-muramic acids, condensation of which with the benzyl ester of L-Ala-D-iGln using the HOSu/DCC method and deprotection afforded the target glycopeptides.

β-Cyclooctyl-, β-cyclodecyl-, and β-cyclopentadecylglycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine were prepared in yields of 39, 18, and 25%, respectively, (calculated for muramic acid) via the reaction of β-cycloalkyl-4,6-O-isopropylidene-N-acetyl-D-muramic acids with the benzyl ester of L-Ala-D-iGln using the HOSu/DCC method followed by deprotection.

Symmetric secondary linear alcohols were proposed as aglycones for the synthesis of lipophilic glycosides of β-N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). Pentadecan-8-ol, nonadecan-10-ol, and tricosan-12-ol were glycosylated by the oxazoline method. Based on the corresponding glucosaminides, alkyl β-glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid were synthesized and coupled with the dipeptide. Deprotection of isopropylidene groups by acidic hydrolysis and catalytic hydrogenolysis of benzyl esters resulted in the target muramyldipeptide glycosides. Nonadecan-10-yl and tricosan-12-yl β-MDPs at doses 2 μg/mice most effectively stimulated antibacterial resistance in mice against Staphylococcus aureus. In contrast to the previously synthesized undecan-6-yl β-MDP, pentadecan-8-yl, nonadecan-10-yl, and tricosan-12-yl β-MDPs demonstrated direct cytotoxicity toward tumor cells K-562 and blood mononuclear cells.

The following glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized: β-4-tert-butylcyclohexyl MDP, β-2-(adamant-1-yl)ethyl MDP, β-2,2-diphenylethyl MDP, and β-2-(p-biphenyl) ethyl MDP. The starting peracetylated β-N-acetylglucosaminides were prepared by the oxazoline method. They were converted into 4,6-O-isopropylidene-N-acetyl-D-muramic acids, which were coupled with L-Ala-D-Glu(NH2)OBn. The target glycopeptides were obtained after their deprotection. The stimulation of the anti-infection resistance of mice against Staphylococcus aureus by the MDP glycosides was studied.

Hexyl, octyl, and cyclohexyl β-glycosides and heptyl and cyclohexyl α-glycosides of muramyl dipeptide (MDP) were synthesized. Tests in vitro and in vivo revealed lower immunostimulating activities of MDP α-glycosides in comparison with the corresponding β-glycosides and MDP itself. In the case of alkyl β-glycosides, differences in hydrocarbon chain lengths (C4–C8) and in aglycone (aliphatic chain and aliphatic or aromatic ring) exerted no substantial effect on the immunostimulating activity.

The synthesis has been effected of alkyl β-glycosides containing spacers with amino and carboxy groups at the end. As “prespacers” we used benzyl and 4-azidobutyl esters of 6-(L-alanyl-D-isoglutaminylamino)hexanoic acid. The use of the butyl and hexadecyl β-glycosides of N-acetylmuramic acid has enabled us to obtain glycopeptides with different hydrophilic—lipophilic balances.

The uninvestigated interferon (IFN)-inducing capacity of glycoside derivatives of N-acetylmuramoyl-L-alanyl-D-isoglutamine (MDP) has been studied. Most MDP glycosides tested in vitro were more active than the reference preparation MDP. Under the in vivo conditions three studied preparations: MDP, a-heptyl-MDP and beta-(2-methyl-3-phenylchromonyl-7)-MDP stimulated production of considerable amount of circulating IFN that evidences for the promising character of their further investigation as preparations immunostimulators.

Anomeric pairs of alpha- and beta-dodecyl, alpha- and beta-(1-pentylhexyl), and alpha- and beta-cyclododecyl glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized. The starting beta-D-glucosaminides were obtained by the oxazoline method, and the corresponding alpha-isomers, by the mercuric iodide-catalyzed glycosylation of alcohols with alpha-glucosaminyl chloride peracetate in nitromethane at -90 degrees C. No reliable differences between the stimulation of mouse resistance to the infection with Staphylococcus aureus (doses of 2, 20, and 200 microg/mouse) and Escherichia coli (doses of 0.05, 1, and 20 microg/mouse) with the MDP alpha- and beta-glycosides were found.

The following glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized: beta-4-tert-butylcyclohexyl MDP, beta-2-(adamant-1-yl)ethyl MDP, beta-2,2-diphenylethyl MDP, and 3-2-(p-biphenyl)ethyl MDP. The starting peracetylated beta-N-acetylglucosaminides were prepared by the oxazoline method. They were converted into 4,6-O-isopropylidene-N-acetyl-D-muramic acids, which were coupled with L-Ala-D-Glu(NH2)OBn. The target glycopeptides were obtained after their deprotection. The stimulation of the antiinfection resistance of mice against Staphylococcus aureus by the MDP glycosides was studied. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.

Hexyl, octyl, and cyclohexyl beta-glycosides and heptyl and cyclohexyl alpha-glycosides of muramyl dipeptide (MDP) were synthesized. Tests in vitro and in vivo revealed lower immunostimulating activities of MDP alpha-glycosides in comparison with the corresponding beta-glycosides and MDP itself. In the case of alkyl beta-glycosides, differences in hydrocarbon chain lengths (C4-C8) and in aglycone (aliphatic chain and aliphatic or aromatic ring) exerted no substantial effect on the immunostimulating activity.

Synthesis of N-acetylmuramyl-L-alanyl-D-isoglutamine phenyl and naphthyl-2 beta-glycosides, novel muramyl dipeptide derivatives with phenolic aglycones, was reported. The starting N-glucosamine aryl glycosides were obtained by glycosylation of phenols with peracetylated alpha-glucosaminyl chloride under the conditions of phase-transfer catalysis and used for the synthesis of 4,6-O-isopropylidene-N-acetylmyramic acid aryl beta-glycosides. Condensation of these derivatives with a dipeptide and subsequent deprotection resulted in the target glycopeptides.

Symmetric secondary linear alcohols were proposed as aglycones for the synthesis of lipophilic beta-glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). Pentadecan-8-ol, nonadecan-10-ol, and tricosan-12-ol were glycosylated by the oxazoline method. Based on the corresponding glucosaminides, alkyl beta-glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid were synthesized and coupled with the dipeptide. Deprotection of isopropylidene groups by acidic hydrolysis and catalytic hydrogenolysis of benzyl esters resulted in the target muramyldipeptide glycosides. Nonadecan-10-yl and tricosan-12-yl [beta]-MDPs at doses 2 microg/mice most effectively stimulated antibacterial resistance in mice against Staphylococcus aureus. In contrast to the previously synthesized undecan-6-yl beta-MDP, pentadecan-8-yl, nonadecan-10-yl, and tricosan-12-yl beta-MDPs demonstrated direct cytotoxicity toward tumor cells E-562 and blood mononuclear cells.

Methyl esters of the cyclohexyl-, phenethyl-, (2-naphthyl)methyl-, and 2′-(1-naphthyl)ethyl β-glycosides of N-acetylmuramyl-L-analyl-D-isoglutamine have been synthesized. The corresponding glycosides of N-acetylglucosamine were obtained by glycosylating the alcohols with the peracetate of α-glucosaminyl chloride in the presence of HgI2, followed by deacetylation. Subsequent benzylidenation and alkylation with α-L-chloropropionic acid led to glycosylmuramic acids, the condensation of which with the dipeptide and final debenzylidenation gave the desired glycopeptides.

Anomeric pairs of alpha- and beta-dodecyl, alpha- and beta-(1-pentylhexyl), and alpha- and beta-cyclododecyl glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized. The starting beta-D-glucosaminides were obtained by the oxazoline method, and the corresponding alpha-isomers, by the mercuric iodide-catalyzed glycosylation of alcohols with alpha-glucosaminyl chloride peracetate in nitromethane at -90 degrees C. No reliable differences between the stimulation of mouse resistance to the infection with Staphylococcus aureus (doses of 2, 20, and 200 microg/mouse) and Escherichia coli (doses of 0.05, 1, and 20 microg/mouse) with the MDP alpha- and beta-glycosides were found.