Parallel solution synthesis of a "Carbohybrid" library designed to inhibit galactose-binding proteins.
Parallel solution S-alkylations of a 1-thio-beta-D-galactopyranoside derivative with Michael acceptors and alpha-chloroketones, followed by ketone reductions, reductive aminations, and acylations were developed to yield a library of 1-thio-beta-D-galactopyranosides carrying small and diverse polar-neutral, hydrophobic, aromatic, cationic, or anionic non-carbohydrate aglycon structures. Screening of the library against a panel of galactose recognizing plant lectins revealed microM inhibitors of toxin A of A. precatorius superior to the reference ligands lactose and N-acetyl lactosamine. Such small, monosaccharide based inhibitors are attractive lead-molecules for therapeutic development, since they are low-molecular, hydrolytically stable and more hydrophobic than natural oligosaccharides.
Nilsson
U J
UJ
Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, Canada.
Fournier
E J
EJ
Fryz
E J
EJ
Hindsgaul
O
O
D002135:Calcium-Binding Proteins; D002241:Carbohydrates / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005690:Galactose / Q000737:chemistry; D006386:Hemagglutination Tests; D007659:Ketones / Q000737:chemistry; D037102:Lectins / Q000187:drug effects / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D033902:Periplasmic Binding Proteins; D013237:Stereoisomerism
D002135:Calcium-Binding Proteins; D002241:Carbohydrates; D007659:Ketones; D037102:Lectins; D009004:Monosaccharide Transport Proteins; D033902:Periplasmic Binding Proteins; C023550:galactose-binding protein; D005690:Galactose