SYNTHESIS AND ENZYME-INHIBITORY ACTIVITY OF NOVEL GLYCOSIDASE INHIBITORS CONTAINING SULFUR AND SELENIUM

The syntheses of novel methyl maltoside analogues containing sulfur in the nonreducing ring and either oxygen, sulfur, or selenium atoms in the interglycosidic linkage are described. The compounds are substrate analogues for glucosidases and are of interest as potential inhibitor s of these enzymes. The syntheses rely on the use of the 4,5,6-tetra-O -acetyl-5-thio-alpha-D-glucopyranosyl trichloroacetimidate 6 as a glyc osyl donor and methyl 2,3,6-tri-O-benzoyl-4-X-alpha-D-glucopyranoside (X = OH, SH, SeH) as glycosyl accepters. The glycosylation reactions a re catalyzed by triethylsilyl triflate. The 5'-thio-4-X-disaccharides are obtained as alpha:beta mixtures of 100:0 (X = O 8), 36:1 (X = S 17 , 18), and 4,5:1 (X = Se 23, 24), in yields of 85%, 55%, and 57%, resp ectively. The notable alpha-selectivity is attributed to the greater t hermodynamic stability of the alpha-isomers. In accordance with this c onclusion, rearrangement of the orthoester 12, formed as a side produc t in the reaction to give the 5'-thiomaltoside, under acid catalysis a ffords the alpha-disaccharide. A reaction employing 6 and methyl 2,3,6 -tri-O-benzyl-alpha-D-glucopyranoside 13 leads to a loss of stereosele ctivity and gives a 1:1.2 alpha:beta mixture of the disaccharides 14 a nd 15. Deprotection of 8, 17, and 23 by transesterification gives the pure methyl maltoside heteroanalogues 1, 2, and 3, respectively. Kinet ic studies indicate that 1, 2, and 3 are competitive inhibitors of the binding of maltose by glucoamylase G2, with K-i values of 1.34, 2.04, and 0.80 mM, respectively. The K-i values for the phenyl selenoglycos ides of alpha-D-glucose 4 and alpha-D-5-thioglucose 5 are 5.88 and 4.0 1 mM, respectively, and the K-m values for the substrates maltose and 4-nitrophenyl alpha-D-glucopyranoside are 1.2 and 3.7 mM, respectively .