Synthesis of stable and selective inhibitors of human galectins-1 and -3.

Abstract The syntheses of glycolytically stable galactosides and lactosides have been made toward the selective inhibition of human galectins-1 and -3. Transition metal-catalyzed cross-coupling reactions were used to create carbon–carbon bond formation (Sonogashira, Suzuki, Heck, Glaser). Additionally, Hantzsch condensation was used to create novel 2-aminothiazoles which reacted with a panel of acylating and sulfonylating reagents. Moreover, dimeric galactosides and lactosides bearing triazoles, regiospecifically prepared using copper-catalyzed Huisgen azide-alkyne [1,3]-dipolar cycloaddition, provided efficient galectins-1 and -3 inhibitors. Best monovalent inhibitor among the tested series was ( E )-methyl 2-phenyl-4-(β- d -galactopyranosyl)-but-2-enoate 15 with inhibitory potency of 313 μM against galectin-1 and best dimers were bis-lactoside 68 and 75 having both inhibitory properties of 160 μM against Galectin-3.