Synthesis of a phenyl thio-beta-D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of effcient and selective monosaccharide inhibitors of galectin-7

The galectins are a family of beta-galactoside-binding proteins that have been implicated in cancer and in. flammation 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-difluoro-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 affi. nity 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 mu M) 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.