Synthesis and immunoadjuvant activities of 2-acetamido-5-O-acetyl-6-O-acyl-2-deoxy-3-O-[(R)-2-propionyl-L-alanyl-D- isoglutamine]-D-glucofuranoses as potential prodrug forms of 6-O-Acyl Derivatives of N-acetylmuramyl dipeptide

Abstract

2-Acetamido-5-O-acetyl-6-O-acyl-2-deoxy-3-O-[(R)-2-propionyl-L-alanyl-D- isoglutamine]-D-glucofuranoses, designed as prodrug forms of the corresponding immunoadjuvant-active 6-O-acyl derivatives of N-acetylmuramyl dipeptide (MDP), were synthesized from benzyl 2-acetamido-2-deoxy-5, 6-O-isopropylidene-beta-D-glucofuranoside and found, when administered to mice in an aqueous medium, to elevate antibody production against bovine serum albumin. The 5,6-di-O-acetyl derivative 8 exhibited activity similar to that of MDP at 50 micrograms/dose. The antibody titer measured for the 5-O-acetyl-6-O-stearoyl compound 9 was comparable to that obtained with 6-O-stearoyl-MDP at 50 micrograms, and both compounds were more active than MDP at 5 micrograms. The more lipophilic 5-O-acetyl-6-O-[2-(behenoyloxy)isobutyryl] compound 10 was considerably more active than MDP at both 50 and 5 micrograms; moreover, its potent adjuvant activity was not diminished at the lower dose. The three 5-O-acetylated 6-O-acylated dipeptidyl furanose derivatives also significantly stimulated production of circulating antibodies against hepatitis B vaccine in mice; titers were comparable to those observed with the alum-adsorbed vaccine. The range of immunoadjuvant activities obtained with 8-10 and control compounds supports a prodrug mechanism for this class of furanoid MDP analogues.