title: Combinatorial approach to N-substituted aminocyclitol libraries by solution-phase parallel synthesis and preliminary evaluation as glucocerebrosidase inhibitors.
abstract: Libraries of N-substituted aminocyclitol derivatives of the scyllo and racemic chiro series by means of parallel solution-phase methodology with the help of robotic technology are described. Chemical diversity has been introduced by reaction of selected scaffolds with a set of aldehydes, acyl chlorides, sulfonyl chlorides, chloroformates, and amines to afford the corresponding amines, amides, sulfonamides, carbamates and ureas, respectively. The optimized methodology has proven excellent, in terms of overall purities of the resulting libraries, for the production of amides. Sulfonamides and carbamates have been obtained in slightly lower purities, while amines afforded modest results. Selected library members have been evaluated as inhibitors of recombinant glucocerebrosidase with K(i) values ranging in the low micromolar scale for the most active members.
authors.affiliation: Research Unit on Bioactive Molecules (RUBAM), Department of Organic and Biological Chemistry, Chemical and Environmental Research Institute of Barcelona (IIQAB-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Serrano
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Martine
authors.initials: M
authors.lastname: Zucco
authors.forename: Gilbert
authors.initials: G
authors.lastname: Emeric
authors.forename: Meritxell
authors.initials: M
authors.lastname: Egido-Gabás
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D006595:Hexosamines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013055:Spectrophotometry, Infrared; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000438:Alcohols; D002219:Carbamates; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D006595:Hexosamines; D013449:Sulfonamides; D014508:Urea; D005962:Glucosylceramidase; C090568:imiglucerase