Competitive inhibition of glycoside hydrolases by 1,3-diamino-1,3-dideoxy-tetritols and their cyclic carbonic and thiocarbonic amides

Abstract

1,3-Diamino-1,3-dideoxy- d-threitol ( 1) and the corresponding 1,3-diamino-1,3-dideoxy- d-erythritol ( 2) were synthesised starting from d-glucose and l-arabinose, respectively. These acyclic diamines inhibited competitively both β- d-glucosidase from sweet almond emulsin and β- d-galactosidase from E. coli with K i-values ranging from 3 to 10 mM. When the suitably blocked diamines were reacted with activated carbonic and thiocarbonic acid derivatives, cyclic urea 5( R)-hydroxy-4( R)-hydroxymethyl-tetrahydropyrimidin-2-one ( 13), 5( S)-hydroxy-4( R)-hydroxymethyl-tetrahydropyrimidin-2-one ( 15) and thiourea 5( S)-hydroxy-4( R)-hydroxymethyl-tetrahydropyrimidin-2-thione ( 18) derivatives were obtained, which conformationally resemble the envelope structure of the d-glucopyranosyl or the d-galactopyranosyl cation. The cyclic carbonamides showed extremely weak competitive inhibition but only with their corresponding enzymes. Compounds 15 and 18 exist, as indicated by 1H NMR spectroscopy, in an unexpected E-conformation with axial substituents. Upon per- O-acetylation the expected conformation with equatorial substituents is adopted.