Showing papers by "Pavla Bojarová published in 2014"
TL;DR: It is proposed that hydrophobicity directed by the alkyl chain length as well as the specificity and bivalency of the LacdiNAc contribute to the inhibition potential of these ligands.
Abstract: A set of sixteen bivalent symmetrical and asymmetrical LacdiNAc dimers containing flexible alkyl linkers were efficiently synthesized by means of chemo-enzymatic synthesis, using the versatile potential of the Y284L mutant of human placental β1,4-galactosyltransferase-1. LacdiNAc was confirmed to be a specific ligand for human galectin-3 contrary to human galectin-1. The compounds were tested as ligands for human galectin-3 in competitive binding assays and compared to a monovalent LacdiNAc standard. Molecular modeling was performed to calculate approximate length of respective ligands and its relation to their inhibitory capacity. The best performance was observed in symmetrical compounds carrying two LacdiNAc units connected with a hydrophobic linker of sufficient length (alkyl chain n ≥ 6). Here, the IC50 value was about three times lower than that of the monovalent standard. Our results propose that hydrophobicity directed by the alkyl chain length as well as the specificity and bivalency of the LacdiNAc contribute to the inhibition potential of these ligands. Though only slightly pronounced in this case, higher multivalency is a promising feature in the design of optimized ligands for galectin-3.
28 citations
TL;DR: The design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position are focused on, which confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers.
Abstract: NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetyl- hexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20) and β-N-acetylglucosaminidases from Bacteroides thetaiotaomicron and humans (both GH84). From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNAc-thiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.
14 citations