title: Synthesis of N-substituted ε-hexonolactams as pharmacological chaperones for the treatment of N370S mutant Gaucher disease.
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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Wang
authors.forename: Gabriele
authors.initials: G
authors.lastname: Twigg
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Siwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.forename: Li-He
authors.initials: LH
authors.lastname: Zhang
authors.forename: Xin-Shan
authors.initials: XS
authors.lastname: Ye
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005962:Glucosylceramidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D050111:Imino Sugars; D007769:Lactams; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin; D005962:Glucosylceramidase