Synthesis of stable and selective inhibitors of human galectins-1 and -3.
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-(beta-D-galactopyranosyl)-but-2-enoate 15 with inhibitory potency of 313 microM against galectin-1 and best dimers were bis-lactoside 68 and 75 having both inhibitory properties of 160 microM against Galectin-3.
Giguère
Denis
D
Department of Chemistry, Université du Québec à Montréal, PO Box 8888, Succ. Centre-Ville, Montreal, Que., Canada H3C 3P8.
Bonin
Marc-André
MA
Cloutier
Philipe
P
Patnam
Ramesh
R
St-Pierre
Christian
C
Sato
Sachiko
S
Roy
René
R
D004355:Drug Stability; D005697:Galactosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037483:Galectin 1 / Q000037:antagonists & inhibitors*; D037502:Galectin 3 / Q000037:antagonists & inhibitors*; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
D005697:Galactosides; D037483:Galectin 1; D037502:Galectin 3; D006027:Glycosides; C008245:lactosides