Synthesis and biological activities of N-acetyl-1-thiomuramoyl-L-alanyl-D-isoglutamine and some of its lipophilic derivatives.
N-Acetyl-1-thiomuramoyl-L-alanyl-D-isoglutamine and some lipophilic analogs were synthesized from benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-3-O-[D-1-(methoxycarbonyl)ethyl ]- alpha-D-glucopyranoside (1). O-Debenzoylation of 2, derived from 1 by oxidation, gave 2-acetamido-2-deoxy-4,6-O-isopropylidene-3-O-[D-1-(methoxycarbonyl)ethyl ]-D-glucopyranose (3). Condensation of the alkoxy-tris(dimethylamino)phosphonium chloride (4), formed from 3 by the action of carbon tetrachloride and tris(dimethylamino)phosphine, with potassium thioacetate afforded 2-acetamido-1-S-acetyl-2-deoxy-4,6-O-isopropylidene-3-O-[ D-1-(methoxycarbonyl)ethyl]-1-thio-beta-D-glucopyranose (8). Coupling of the acid 9, obtained from 8 by hydrolysis and subsequent S-acetylation, with the methyl ester of L-alanyl-D-isoglutamine gave N-[2-O-(2-acetamido-1-S-acetyl-2,3-dideoxy-4,6-O- isopropylidene-1-thio-beta-D-glucopyranose-3-yl)-D-lactoyl]-L-alan yl-D- isoglutamine methyl ester (10), which was converted, via O-deisopropylidenation, S-deacetylation, and de-esterification, into the N-acetyl-1-thiomuramoyl dipeptide. Condensation of 11 (derived from 10 by S-deacetylation) and of 12 (obtained from 10 by S-deacetylation and de-esterification) with various acyl chlorides yielded the corresponding 1-S-acyl-N-acetylmuramoyl-L-alanyl-D-isoglutamine derivatives, which were converted into the desired, lipophilic 1-thiomuramoyl dipeptides by cleavage of the isopropylidene group. Condensation of 11 with the alkyl bromides yielded the 1-S-alkyl derivatives, which were also converted, via O-deisopropylidenation and de-esterification, into the corresponding 1-S-alkylmuramoyl dipeptides. The biological activities were examined in guinea-pigs and mice.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004342:Drug Hypersensitivity; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed / Q000139:chemically induced; D051379:Mice; D008807:Mice, Inbred BALB C
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C040416:N-acetyl-thiomuramyl-alanyl-isoglutamine