Synthetic Galectin Inhibitors Selective O-galactosyl aldoximes, multivalent lactosides and galactose-mimicking mannosides

Abstract: This thesis describes the design, synthesis and evaluation of synthetic inhibitors for the carbohydrate binding proteins called galectins. Potent and selective inhibitors can be used as important research tools in the endeavor to chart the true role of galectins in biological events such as cancer and inflammation and possibly as lead for future galectin targeting drugs. A panel of O-galactosyl aldoximes was synthesized and inhibitors with high affinity and selectivity for galectin-3 and -7 were identified. The best inhibitor for galectin-3, O-(?-D-galactopyranosyl)-indole-3-carbaldoxime, was combined with previously optimized galectin-3 targeting triazoles, in a fragment based approach, to give 3C-triazol-1-yl-O-galactopyranosyl aldoximes with high affinity and selectivity for galectin-3 (Kd down to 11 µM). Furthermore, a glycoside clustering effect was observed for multivalent lactose containing inhibitors and galectin-1. The mechanisms behind this were investigated using mutated galectin-1, lacking the possibility to dimerize. Finally, 1H-1,2,3-triazol-1-yl mannosides, with synthetic advantages over galactose based inhibitors, were synthesized and the 4-benzylaminocarbonyl-1H-1,2,3-triazol-1-yl ?-D-mannopyranoside (Kd=540 µM, for galectin-9N) compared favorably with its galactoside counterpart.