Abstract
A series of N-substituted ε-hexonolactams have been designed and prepared by a concise route with a tandem ring-expansion reaction as the key step. Some of the N-substituted ε-hexonolactams show better enhancements to N370S mutant β-glucocerebrosidase activity than NB-DNJ and NN-DNJ. Both the experimental results and computational studies highlight the importance of the carbonyl group for stabilizing protein folds in the mutant enzyme. The structure-activity relationships are also discussed. These novel N-alkylated iminosugars are promising pharmacological chaperones for the treatment of N370S mutant Gaucher disease.
This journal is © The Royal Society of Chemistry 2012
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Deoxynojirimycin / analogs & derivatives
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1-Deoxynojirimycin / pharmacology
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Cell Survival / drug effects
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Cells, Cultured
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Enzyme Activation
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Enzyme Activators / chemical synthesis*
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Enzyme Activators / pharmacology
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Gaucher Disease / drug therapy*
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Gaucher Disease / enzymology
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Gaucher Disease / pathology
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Glucosylceramidase / chemistry
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Glucosylceramidase / genetics
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Glucosylceramidase / metabolism*
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Humans
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Imino Sugars / chemical synthesis*
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Imino Sugars / pharmacology
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Kinetics
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Lactams / chemical synthesis*
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Lactams / pharmacology
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Models, Molecular
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Mutation
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Protein Folding
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Structure-Activity Relationship
Substances
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Enzyme Activators
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Imino Sugars
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Lactams
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N-nonyl-1-deoxynojirimycin
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1-Deoxynojirimycin
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Glucosylceramidase