Synthesis and deconvolution of the first combinatorial library of glycosidase inhibitors.
A combinatorial library of 125 compounds with a structure consisting of 1-azafagomine linked at N-1 via an acetic acid linker to a variable tripeptide was synthesised. The library was synthesised by Merrifield split and mix synthesis of the peptide, followed by capping with chloroacetate, regioselective nucleophilic substitution with 1-azafagomine and cleavage from the polymeric support. The library was screened for inhibition of beta-glucosidase, alpha-glucosidase and glycogen phosphorylase and found to display beta-glucosidase inhibition. Deconvolution of the library revealed that some inhibition was caused by all library members but the strongest inhibitor was clearly a compound having three hydroxyproline residues in the peptide fragment. This compound was a weaker but more selective inhibitor than 1-azafagomine itself.
Lohse
A
A
Department of Chemistry, Aarhus University, Denmark.
Jensen
K B
KB
Lundgren
K
K
Bols
M
M
D002240:Carbohydrate Sequence; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D013057:Spectrum Analysis
D004791:Enzyme Inhibitors; D006026:Glycoside Hydrolases