Volume 23, Issue 3 - Special Issue on Carbohydrate Chemistry/Glycoscience

Recent years have seen tremendous development in the design and synthesis of boron-based compounds as potential therapeutics and for detection applications. The present review highlights the most recent development of these boron-based small molecules, covering clinically used ixazomib, tavaborole, crisaborole and other molecules from 2013 to 2016.

The modification of the ribofuranose in nucleic acids is a widespread method of manipulating the activity of nucleic acids. These alterations, however, impact the local conformation and chemical reactivity of the sugar. Changes in the conformation and dynamics of the sugar moiety alter the local and potentially global structure and plasticity of nucleic acids, which in turn contributes to recognition, binding of ligands and enzymatic activity of proteins. This review article introduces the conformational properties of the (deoxy)ribofuranose ring and then explores sugar modifications and how they impact local and global structure and dynamics in nucleic acids.

The 5-nitrosalicylate ester of 2-acetamidophenylboronic acid (C 15 H 10 BN 2 O 6 ) is formed under crystallization conditions from the 5-nitrosalicylate ester of 2-aminophenylboronic acid. The boron at the center of this structure exists as a tetrahedral complex produced by a dative bond with the amide carbonyl. The perpendicular shape produces an unusual packing structure including a bifurcated hydrogen bond between the amide hydrogen and carbonyl groups on two neighboring molecules. We propose that this reaction occurs due to increased Lewis acidity of the nitrosalicylate ester of 2-aminophenylboronic acid.

Two 2,6-pyridinedicarboxamide derivatives containing arylboronic acid fragments were prepared and fully characterized including X-ray crystal diffraction analysis of a pinacol ester. These compounds are potential bifunctional receptors for sugars and anions. Acid dissociation and stability constants for complexation of both receptors with glucose and fructose were determined by potentiometric titrations in aqueous DMSO. Also, binding of alizarin red S indicator was studied spectrophotometrically and a highly sensitive detection of fructose by an indicator displacement assay was proposed. Complexation with anions was studied by 1 H NMR titrations in DMSO- d 6 . Binding of acetate anion occurs only via hydrogen bonding to OH groups of boronic acid fragments and does not affect signals of NH protons but chloride anion induces large shift of the signals of NH protons and small shifts of the signals of OH groups. This behavior makes possible anion discrimination based on preference in the type of binding site rather than simply on anion basicity as is typical for majority of neutral hydrogen bonding anion receptors.

The synthesis of a biotinylated bivalent zanamivir analog as a probe for influenza viruses is reported. The compound was used in a ‘glycan’ based sandwich assay; where glycans were immobilized on glass slides to capture strains of influenza A H1N1, A/Brisbane/59/2007 virus; the biotinylated bivalent zanamivir analog-labeled streptavidin complex was used as reporter. This research strongly suggests that glycans can be used for capturing and reporting influenza viruses and the biotinylated compounds can be used as probes for capturing and isolating influenza viruses from complex mixtures.

We report here the first chemical synthesis of silodosin glucuronide, a metabolite of the α 1A -adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O -glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated d -glucuronosyl N -phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.

4-Trifluoromethylpyridine derivatives 4–8 represent good candidates for the discovery of new antibacterial agents. Fluorinated pyridine nucleosides 4–7 and non-nucleoside analogues 8a,b were synthesized and evaluated for their antibacterial activities against Staphylococcus aureus, Bacillus infantis, Escherichia coli and Stenotrophomonas maltophilia. The minimum inhibitory concentrations (MICs) of the new nucleosides 4–7 range from 1.3 to 4.9 μg/mL and MICs of fluoroaryl derivatives 8a,b are in the range of 1.8–5.5 μg/mL. Activity of amoxicillin, the reference drug, is 1.0–2.0 μg/mL under similar conditions.

The preparation of eight 2,3-unsaturated O -glycosides from D-glycals and alcohols, using montmorillonite K-10 as an acid catalyst, is described. The Ferrier rearrangement products were obtained in good yields using conventional heating and microwave irradiation but the reaction time was substantially reduced employing the latter procedure. The yields were slightly lower under microwave exposure. Five of the di- O -acetylated products were deacetylated to the glycosides in excellent yields. The acetylated products possess good anti-inflammatory property suggesting that the acetyl group plays an important role in reducing the inflammation. Among the compounds tested, glycosides containing thiophene as an aglycone present much better inflammation reducing characteristics than the analogues without this function.

Various β-D-glucopyranosyl and β-D-xylopyranosyl hydroxybenzoates were efficiently prepared from 2,3,4,6-tetra- O -acetyl-α-D-glucopyranosyl bromide (TAGB) or 2,3,4-tri- O -acetyl-α-D-xylopyranosyl bromide (TAXB), respectively, by amine-promoted glycosylation. Regioselective deacetylation of the resulting acetylated β-D-gluco- and β-D-xylopyranosyl hydroxybenzoates was investigated using Novozym 435 as a lipase catalyst. In the case of β-D-glucopyranosyl hydroxybenzoates, Novozym 435-catalyzed deacetylation is regioselective at C-4 and C-6 positions. On the other hand, β-D-xylopyranosyl hydroxybenzoates are deacetylated only at the C-4 position. Antioxidant activities of free hydroxybenzoic acids and the respective β-D-gluco- and β-D-xylopyranosyl hydroxybenzoates were evaluated by DPPH˙ radical scavenging as well as their inhibitory effect on autoxidation of bulk methyl linoleate. The β-D-xylopyranosyl protocatechoate, as well as quercetin and α-tochopherol, show high antioxidant activity for the radical scavenging activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH˙). In bulk methyl linoleate, the antioxidant activities of β-D-gluco- and β-D-xylopyranosyl protocatechoates are higher than that of α-tocopherol.

Eight new sugar-substituted isoxazoles were synthesized by a 1,3-dipolar cycloaddition reaction of aromatic nitrile oxides with carbohydrate-substituted alkynes. Products were screened for antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain. Four compounds, 5e–h , significantly inhibit growth of the bacterial strain with a minimum inhibitory concentration (MIC) of 3.125 μg/mL.

New C2-glycosyl triazole derivatives 6a–l were synthesized by cyclization of glycosyl acylthiosemicarbazides 5 in refluxing 3 N sodium hydroxide aqueous solution. Substrates 5 were obtained by the reaction of glycosyl isothiocyanate 3 with various hydrazides. The acetylcholinesterase (AChE) inhibitory activities of compounds 6 were tested by Ellman’s method. Compounds that exhibited over 85% inhibition were subsequently evaluated for the IC 50 values. Compound 6f possesses the best acetylcholinesterase-inhibition activity with IC 50 of 1.46±0.25 μg / mL.

Aminophenylboronic acid (ABA) modified bovine serum albumin (BSA) was prepared as neolectin and its interactions with oligosaccharides and glycopolymer were studied by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). The conjugation between the primary amine group of the ABA molecule and lysine residues on BSA was performed with an adipate-based strategy to afford the synthetic neoprotein. The number of ABA molecules loaded to BSA surface was determined by matrix-assisted laser desorption/ionization – time of flight (MALDI-TOF) mass spectrometry. In the BSA-ABA and sugar interaction study, no signal was observed for both the SPR and ITC sensor platform using monosaccharides as the analyte, indicating a weak binding affnity, while the galactose modified polymer showed an enhanced response. The binding affinities of the galactosyl-polymer to BSA-ABA from SPR and ITC data were in the micromolar range.