ABSTRACT
In the course of chemical modification of alpha-fucosidase inhibitors of 5a-carba-fucopyranosylamine type, an N-dodecyl derivative of the enantiomer 6-deoxy-5a-carba-beta-D-galactopyranosylamine demonstrated very strong inhibition of beta-galactosidase and beta-glucosidase. This finding led us to synthesize corresponding 6-hydroxy compounds, in order to elucidate structure-activity relationships for inhibitors of this type. Among four N-alkyl-5a-carba-beta-D-galactopyranosylamines prepared, the N-octyl derivative could be demonstrated to possess moderate activity toward alpha- and beta-galactosidases, and beta-glucosidase.
Subject(s)
Galactosamine/analogs & derivatives , Glycoside Hydrolases/antagonists & inhibitors , Galactosamine/chemical synthesis , Galactosamine/pharmacology , Inhibitory Concentration 50 , Structure-Activity Relationship , beta-Galactosidase/antagonists & inhibitors , beta-Glucosidase/antagonists & inhibitorsABSTRACT
Since glycosidase and glycosyltransferase inhibitors, composed of carba-sugars, have recently attracted much attention, it is desirable to develop effective preparative routes for provision of new carba-sugar derivatives of potential biological interest. 1,2:3,6-Dianhydro-5a-carba-alpha-glucopyranose was here chosen for study of synthetic utility, and demonstrated to be a promising intermediate for supplying several carba-beta-glycosylamines and N-linked dicarba-oligosaccharides. An N-linked 5a,5a'-dicarbalactose derivative obtained here was found to be a strong alpha-galactosidase inhibitor (IC50 1.2 microM, green coffee beans).
Subject(s)
Alkanes/chemistry , Amino Sugars/chemical synthesis , Disaccharides/chemical synthesis , Galactose/chemical synthesis , Glycoside Hydrolases/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemistry , Amino Sugars/chemistry , Disaccharides/chemistry , Galactose/chemistry , Glycoside Hydrolases/chemistryABSTRACT
Chemical modification of 5a-carba-beta-DL-fucopyranosylamine (3) generated six N-substituted derivatives 9a-f, among which N-octyl 9b, decyl 9c, and phenylbutyl ones 9f were found to be very strong beta-galactosidase as well as beta-glucosidase inhibitors. The inhibitory activity appeared attributable to D-enantiomers from biological assays of prepared L-enantiomers. Therefore, 6-deoxy-5a-carba-beta-D-galactopyranosylamine (D-3) might be a promising lead compound for further design of new carba sugar-type beta-galactosidase inhibitors.
Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosidases/antagonists & inhibitors , Amines/chemistry , Enzyme Inhibitors/chemistryABSTRACT
Methyl 5a'-carba-beta-lactoside, imino-linked, has been shown to possess potent and specific inhibitory activity (IC50 = 185 microM) toward rat recombinant alpha2,3-sialyltransferase.
