Synthesis of 4-deoxy analogues of 2-acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-D-xylose and their effects on glycoconjugate biosynthesis.
4-Deoxy analogues of 2-acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-D-xylose were synthesized and evaluated as inhibitors of glycoconjugate biosynthesis. Methyl 2-acetamido-2,4-dideoxy-beta-D-xylo-hexopyranoside (11) showed a reduction in [3H]GlcN and [14C]Leu incorporation into hepatocyte cellular glycoconjugates by 89 and 88%, of the control cells, respectively, at 20 mM, whereas the free sugars, 2-acetamido-2,4-dideoxy-alpha,beta-D-xylo-hexopyranoses (15), showed a reduction of [3H]GlcN and [14C]Leu incorporation by 75 and 64%, respectively, at 20 mM. The acetylated analogues of 11 and 15, namely methyl 2-acetamido-3,6-di-O-acetyl-2,4-dideoxy-beta-D-xylo-hexopyranoside and 2-acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy-alpha,beta-D-xylo-hexopyra noses, showed a greater inhibition of [3H]GlcN and [14C]Leu incorporation at 1 mM compared with their non-acetylated counterparts, but were toxic to hepatocytes at concentrations of 10 and 20 mM. Corresponding derivatives of 2-acetamido-2,4-dideoxy-L-threo-pentopyranose showed no biological effect up to 20 mM, suggesting that the C-6 substituent is important for the biological activity.
Berkin
A
A
Department of Chemistry, Queen's University, Kingston, Ont., Canada.
Szarek
M A
MA
Plenkiewicz
J
J
Szarek
W A
WA
Kisilevsky
R
R
D000117:Acetylglucosamine / Q000031:analogs & derivatives; D000818:Animals; D002236:Carbohydrate Conformation; D002478:Cells, Cultured; D003837:Deoxy Sugars / Q000138:chemical synthesis* / Q000494:pharmacology; D006001:Glycoconjugates / Q000096:biosynthesis*; D007930:Leucine / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D014994:Xylose / Q000031:analogs & derivatives
D003837:Deoxy Sugars; D006001:Glycoconjugates; D014994:Xylose; D007930:Leucine; D000117:Acetylglucosamine