Structure-activity relationships in aminocyclopentitol glycosidase inhibitors.
Aminocyclopentitol analogs of beta-D-glucose, beta-D-galactose and alpha-D-galactose bearing alkyl substituents as aglycon mimics on the amine function were prepared and tested for inhibition of various glycosidases. N-benzyl-beta-D-gluco derivatives 1-4 and N-benzyl-beta-D-galacto derivative 5 inhibited beta-galactosidase and beta-glucosidase. N-benzyl-alpha-D-galacto aminocyclopentitol 6 strongly inhibited alpha-galactosidase. The inhibitory activities observed were generally stronger compared to those of their primary amine analogs. A structure-activity relationship analysis was carried out including data from thirty-five different aminocyclopentitol glycosidase inhibitors. The strongest inhibitions reported for any enzyme were associated with a perfect stereochemical match between aminocyclopentitol and glycosidase, including the alpha- or beta-configuration of the amino-group corresponding to the enzyme's anomeric selectivity.
Dickson
Lucas Gartenmann
LG
Department of Chemistry & Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Leroy
Emmanuel
E
Reymond
Jean-Louis
JL
D000605:Amino Alcohols / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005959:Glucosidases / Q000037:antagonists & inhibitors*; D006801:Humans; D018716:Molecular Mimicry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000605:Amino Alcohols; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D005959:Glucosidases