APPROACH TO TRANSITION-STATE ANALOG OF GL YCOSYLTRANSFERASE REACTION - DESIGN AND SYNTHESIS OF SELECTIVE INHIBITOR OF BETA-1,4-GALACTOSYLTRANSFERASE

In order to create specific inhibitors against glycosyltransferases, t ethering glycosyl donor to acceptor was planned. Mono-O-methylated UDP -Gal and related analogues were synthesized, and their behaviors towar d beta-1, 4-galactosyltransferase were examined. The allowance for the O-methylation of Gal moiety was decreased in the following order:2-, 3-, 4- and 6-positions and it was suggested that the modification at t he 2-position does not affect the affinity but retards the reaction ra te by preventing the conformational change to the transition state, wh ich develops so-called dynamic binding. Modification of the glycosyl a cceptor (GlcNAc) moiety showed the tethering probability in the 3'- an d 6'-positions. Bisubstrate tricomponent analogues linked through 2,6' -methylene and 2,6'-ethylene groups were synthesized and found to be p otent inhibitors against bovine GlcNAc: beta-1,4-galactosyltransferase , with K-i values of 1.35 and 1.95 mu M, respectively, for the accepto r.