Synthesis of a phenyl thio-β-D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene:: discovery of effcient and selective monosaccharide inhibitors of galectin-7
Synthesis of a phenyl thio-β-D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene:: discovery of effcient and selective monosaccharide inhibitors of galectin-7
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DOI：
10.1039/b502354h
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Nilsson, UJ
中科院分区：
文献类型：
--
作者：
Cumpstey, I;Carlsson, S;Nilsson, UJ
半乳糖凝集素是一个β-半乳糖苷结合蛋白家族，其与癌症和糖尿病有关。燃烧过程。在此，我们报告了28种化合物的文库的合成，所述化合物被测试用于结合半乳糖凝集素-1、-3、-7、-8N和-9N。1，5-二氟-2，4-二硝基苯与半乳糖硫醇发生芳香亲核取代反应，得到5-二氟-2，4-二硝基苯基-2，3，4，6-四-O-乙酰基-1-硫代-β-D-吡喃半乳糖苷。然后以二维方式对这种多功能中间体进行修饰：通过进一步取代第二个。通过胺或硫醇，或通过硝基的还原和所得胺的酰化，或通过这两者来氟化。然后脱乙酰化得到芳香族β-半乳糖苷的文库，其显示出对不同半乳糖凝集素的可变抑制活性，如通过用荧光偏振测定筛选所示。特别有效的抑制剂被发现对半乳糖凝集素-7，而不太令人印象深刻的增强抑制剂亲和力。半乳糖凝集素-1、-3、-8 N和-9 N的特异性高于甲基β-D-吡喃半乳糖苷。对半乳糖凝集素-7的最佳抑制剂显示出比β-甲基半乳糖苷（K-d 4.8 mM）和未取代的β-苯基硫代半乳糖苷（非抑制性）显著更高的亲和力（K-d低至140 μ M）。针对半乳糖凝集素-7的最佳抑制剂对其他半乳糖凝集素较差，因此具有作为用于剖析半乳糖凝集素-7的生物学功能的结构简单和选择性工具的潜力。
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.