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

In English

Författare

Summary, in English

The galectins are a family of -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--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 -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 -D-galactopyranoside were found for galectin-1, -3, -8N and -9N. The best inhibitors against galectin-7 showed significantly higher affinity (Kd as low as 140 µM) than both -methyl galactoside (Kd 4.8 mM) and the unsubstituted -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.

Publiceringsår

2005

Språk

Engelska

Sidor

1922-1932

Publikation/Tidskrift/Serie

Organic and Biomolecular Chemistry

Volym

3

Issue

10

Dokumenttyp

Artikel i tidskrift

Förlag

Royal Society of Chemistry

Ämne

  • Organic Chemistry

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1477-0539