Analogues of disaccharides and glycosides containing a cyclic guanidinium structure show varying inhibitory effects on glycoside hydrolases

By condensation of 1,3-diamino-2,4-(R)-O-benzylidene-1,3-dideoxy-d-erythritol (3) and 1,3-diamino-2,4-di-O-benzyl-1,3-dideoxy-d-threitol (4) with methyl 2,3,6-tri-O-benzyl-4-deoxy-4-isothiocyanato-β-d-glucopyranoside (9) the (1 → 4)-linked disaccharide analogues 4-deoxy-4-[(4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,4,5,6-tetrahydropyrimidin-2-yl]amino-α, β-d-glucopyranose hydrochloride (15) and 4-deoxy-4-[(4R,5R)-5-hydroxy-4-(hydroxymethyl)-1,4,5,6-tetrahydropyrimidin-2-yl]amino-α,β-d-glucopyranose hydrochloride (18) were synthesized. By the same reaction sequence, using 3 and methyl isothiocyanate, the glycoside analogue (4R,5S)-5-hydroxy-4-(hydroxymethyl)-2-methylamino-1,4,5,6-tetrahydropyrimidine hydrochloride (20) was obtained. All compounds possess in their ‘glyconic’ moiety the flat guanidinium group, mimicking a glucopyranosyl cation. Together with the previously synthesized (1 → 6)-linked disaccharide analogues 6-deoxy-6-[(4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,4,5,6-tetrahydropyrimidin-2-yl]amino-α,β-d-glucopyranose hydrochloride (1) and 6-deoxy-6-[(4R,5R)-5-hydroxy-4-(hydroxymethyl)-1,4,5,6-tetrahydropyrimidin-2-yl]amino-α,β-d-glucopyranose hydrochloride (2), a possible inhibitory effect on the action of α-d-glucosidase, β-d-glucosidase, α-d-galactosidase, and β-d-galactosidase was investigated. All compounds, except 20 with α-d-glucosidase where no inhibition could be detected, showed either competitive or mixed competitive inhibition with all enzymes. The effects of the disaccharide analogues were generally weaker as compared to the effect of the previously synthesized configurationally related nitrophenyl glycoside analogues (4R,5S)-5-hydroxy-4-(hydroxymethyl)-2-(p-nitrophenyl)amino-1,4,5,6-tetrahydropyrimidine hydrochloride (21) and (4R,5R)-5-hydroxy-4-(hydroxymethyl)-2-(p-nitrophenyl)amino-1,4,5,6-tetrahydropyrimidine hydrochloride (22). On the basis of experimental results, different binding modes of competitive inhibitors to the active site of corresponding enzymes are discussed.