The first C-glycosidic analogue of a novel galactosyltransferase inhibitor.
Structural analogues and mimics of the natural sugar-nucleotide UDP-galactose (UDP-Gal) are sought after as chemical tools for glycobiology and drug discovery. We have recently developed a novel class of galactosyltransferase (GalT) inhibitors derived from UDP-Gal, bearing an additional substituent at the 5-position of the uracil base. Herein we report the first C-glycosidic derivative of this new class of GalT inhibitors. We describe a practical convergent synthesis of the new UDP-C-Gal derivative, including a systematic study into the use of radical chemistry for the preparation of galactosyl ethylphosphonate, a key synthetic intermediate. The new inhibitor showed activity against a bacterial UDP-Gal 4'-epimerase at micromolar concentrations. This is the first example of a base-modified UDP-sugar as an inhibitor of a UDP-sugar-dependent enzyme which is not a glycosyltransferase, and these results may therefore have implications for the design of inhibitors of these enzymes in the future.
School of Pharmacy, University of East Anglia, Norwich, UK NR4 7TJ.
Karine
K
Descroix
Gerd K
GK
Wagner
D055162:Biocatalysis; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D048249:Streptococcus thermophilus / Q000201:enzymology*; D014531:Uridine Diphosphate Galactose / Q000031:analogs & derivatives* / Q000737:chemistry
D014531:Uridine Diphosphate Galactose; D005700:Galactosyltransferases