Abstract
Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-C-methyl-gulopyranoside derivatives and their evaluation as galectin inhibitors. Methyl 3-deoxy-3-C-(hydroxymethyl)-β-d-gulopyranoside showed 7-fold better affinity for galectin-1 than the natural monosaccharide fragment analog methyl β-d-galactopyranoside, as well as a high selectivity over galectin-2, 3, 4, 7, 8, and 9. Derivatization of the 3-C-hydroxymethyl into amides gave gulosides with improved selectivities and affinities; methyl 3-deoxy-3-C-(methyl-2,3,4,5,6-pentafluorobenzamide)-β-d-gulopyranoside had Kd 700 µM for galectin-1, while not binding any other galectin.
Highlights
IntroductionGalectins are an evolutionary ancient family of small soluble proteins with affinity for β-d-galactopyranoside-containing glycoconjugates and a conserved amino acid sequence motif [1,2]
Galectins are an evolutionary ancient family of small soluble proteins with affinity for β-d-galactopyranoside-containing glycoconjugates and a conserved amino acid sequence motif [1,2].By their carbohydrate-binding activity they can cross-link glycoproteins, resulting in a variety of effects, such as regulation of cell adhesion, intracellular glycoprotein traffic, and cell signaling [3,4,5]
The vary synthesis of galectins, the 3-C-methyl-gulo derivatives initiated by Dess–Martin periodinane previous inhibitor has derivatized the positions on galactose not engaged by11 subsite
Summary
Galectins are an evolutionary ancient family of small soluble proteins with affinity for β-d-galactopyranoside-containing glycoconjugates and a conserved amino acid sequence motif [1,2] By their carbohydrate-binding activity they can cross-link glycoproteins, resulting in a variety of effects, such as regulation of cell adhesion, intracellular glycoprotein traffic, and cell signaling [3,4,5]. These effects in turn affect cell behavior in inflammation, immunity and cancer, and galectins appear to be rate limiting in some such pathophysiological conditions, e.g., based on effects in null mutant mice and other model systems [6,7,8,9,10]. There is an important need for selective galectin-inhibitors, that, for example, distinguish between the two most studied galectins in humans, galectin-1 and galectin-3
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