ABSTRACT
The design and synthesis of several beta-1,4-galactosyltransferase inhibitors are reported. Mimics of the pyrophosphate-Mn2+ complex were the focus of the design. Malonic, tartaric, and monosaccharide moieties were used as replacements of the pyrophosphate moiety, and galactose or azasugars with potent galactosidase inhibitory activity were used as the 'donor' component. Compound 6, in which glucose was used as the pyrophosphate-Mn2+ complex mimic and galactose as the 'donor' component, showed the best inhibitory activity towards the transferase with a Ki of 119.6 microM.
Subject(s)
Aminoglycosides , Diphosphates/metabolism , Enzyme Inhibitors/chemical synthesis , Fucosyltransferases/metabolism , N-Acetyllactosamine Synthase/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Binding Sites , Diphosphates/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Malonates/chemistry , Manganese/metabolism , Monosaccharides/chemistry , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/metabolism , Substrate Specificity , Tartrates/chemistry , Tunicamycin/chemical synthesis , Tunicamycin/chemistry , Tunicamycin/metabolismABSTRACT
Five-membered ring azasugars with the L-rhamnose configuration were synthesized as inhibitors of alpha-L-rhamnosidase from Penicillium decumbens. All compounds tested were in the microM or sub-microM range. Substitution at the nitrogen shifted the inhibition mechanism from mixed to competitive.
