Synthesis of a phenyl thio-beta-D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and selective monosaccharide inhibitors of galectin-7.
The galectins are a family of [small beta]-galactoside-binding proteins that have been implicated in cancer and inflammation processes. Herein, we report the synthesis of a library of 28 compounds that was tested for binding to galectins-1, -3, -7, -8N and -9N. An aromatic nucleophilic substitution reaction between 1,5-difluoro-2,4-dinitrobenzene and a galacto thiol gave 5-fluoro-2,4-dinitrophenyl 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-galactopyranoside. This versatile intermediate was then modified in a two dimensional manner: either by further substitution of the second fluoride by amines or thiols, or by reduction of the nitro groups and acylation of the resulting amines, or both. Deacetylation then gave a library of aromatic beta-galactosides that showed variable inhibitory activity against the different galectins, as shown by screening with a fluorescence-polarisation assay. Particularly efficient inhibitors were found against galectin-7, while less impressive enhancements of inhibitor affinity over methyl beta-D-galactopyranoside were found for galectin-1, -3, -8N and -9N. The best inhibitors against galectin-7 showed significantly higher affinity (K(d) as low as 140 microM) than both beta-methyl galactoside (K(d) 4.8 mM) and the unsubstituted beta-phenyl thiogalactoside (non-inhibitory). The best inhibitors against galectin-7 were poor against the other galectins and thus have potential as structurally simple and selective tools for dissecting biological functions of galectin-7.
Cumpstey
Ian
I
Organic Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden.
Carlsson
Susanne
S
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives* / Q000737:chemistry; D037161:Galectins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000494:pharmacology
D037161:Galectins; C092525:LGALS7 protein, human; D009005:Monosaccharides; C511682:phenyl thio-beta-D-galactopyranoside; D004139:Dinitrofluorobenzene; C002041:1,5-difluoro-2,4-dinitrobenzene