3-nitrophenylboronic Acid Research Articles

Gelatin-based dynamic response antioxidant, anti-inflammatory multifunctional hydrogel for enhanced diabetic wound repair

Diabetic wound therapy presents significant challenges in the clinical environment, where persistent bleeding, disturbed inflammatory regulation, impaired cellular proliferation, and impaired tissue remodeling are major features of diabetic wound healing. However, current treatment strategies need to be considered in the context of the dynamic and complex needs of chronic wound healing. Here, multifunctional dynamic boronic acid cross-linked hydrogels were prepared by the reaction of gelatin (Gel) inoculated with 5-carboxy 3-nitrophenylboronic acid (NPBA) and Epigallocatechin gallate (EGCG) to achieve rapid gelation at pH = 7.4, EGCG could interact electrostatically with cationic antimicrobial peptides (AMP) to achieve the effective loading of AMP in the hydrogels. This hydrogel can be injected and adhered to skin defects in diabetic patients to provide a barrier and rapid hemostasis. In a high glucose microenvironment, the rapid release of AMP effectively kills bacteria, while the responsive release of EGCG eliminates reactive oxygen species (ROS) and promotes macrophage M2 polarization. In addition, the hydrogel had excellent biocompatibility and degradability properties, degraded completely after 3 days of subcutaneous injection, and was non-toxic in H&E staining of major organs and serum liver function indices in mice. This multifunctional injectable hydrogel accelerates diabetic skin wound repair and is a promising dressing for the precise treatment of diabetic wounds.

Luminescent lanthanide metallogel as a sensor array to efficiently discriminate various saccharides

By loading 3-nitrophenylboronic acid (3-NPBA) which can react with saccharide, the fluorescence lanthanide metallogel can emit fluorescence signals at 398, 490 and 546 nm. Thus, a three-dimensional responsive fluorescence sensor array (H6L/Tb3+/3-NPBA) was prepared to recognize saccharides. Due to the typical pH responsiveness of the fluorescence behavior of the sensor array, it is suitable for H+ generation systems, such as the reaction of 3-NPBA with cis-diol of saccharides. The response of fluorescence signal intensity to 15 different saccharides was measured, and the qualitative discrimination of those saccharides was investigated by principal component analysis (PCA). The results showed that PCA elliptic clusters did not overlap, even though the concentration of the saccharides was as low as 3 mmol/L, and the discrimination rate of each saccharide reached 100 %. The “double blind” experiment indicated that the sensor system has good ability to discriminate unknown component samples. Furthermore, the discrimination rate of fructose/glucose mixtures with varied mole ratios also reached 100 %. The method of Euclidean distance confirmed that there was a good linear correlation between PCA elliptic clusters of fructose and its concentration, which could realize the quantitative analysis of fructose. The results of PCA indicated that the elliptic clusters of tea drinks with various sugars and commercially available sugar-containing drinks were loosely distributed, which further confirmed that the sensor system can effectively discriminate the saccharides under the interference of complex components.

Boronic derivatization-based strategy for monoacylglycerol identification, isomer annotation and quantification

Monoacylglycerols (MAGs) are important signaling molecules involved in various diseases. However, it is challenge for direct detection of MAGs and isomers. Additionally, difficulties in isomer annotation hinders the comprehensive profiling of MAGs and hampers revealing isomers' contributions to diseases. Herein, a boronic derivatization-based strategy was developed for unambiguous identification, isomer annotation and quantification of MAGs in biological samples. 3-Nitrophenylboronic acid was selected as the derivatization reagent owing to its rapid and selective reactivity toward cis-diol moiety. First, a prediction model was established for MAG identification by the integration of m/z, isotopic distribution of boron, and retention time attributed by the carbon chain length and number of double bonds, which solved the difficulty of obtaining MAG standards. In addition, the designed derivatization reaction enabled the capture of thermally unstable sn-2 MAG isomers to ensure the chromatographic separation and direct MS detection. What's more, distinguished fragmentation patterns were discovered for derivatized MAG isomers, which allowed a novel and unambiguous isomer annotation. Furthermore, by considering the availability of standards, the quantification of MAGs was based on the development of calibration curves or relative quantification by internal standard. On this basis, the developed strategy was utilized for MAG identification and quantification in breast cancer samples, which suggested that MAGs could be regarded as potential biomarkers in breast cancer diagnosis or as indicators to trace the process of chemotherapy. It also helped make the puzzle complete by revealing that only one single isomer associated with the onset of disease was possible, instead of regarding them as a whole. Therefore, the boronic derivatization-based strategy facilitated the unambiguous identification, annotation and quantification of MAGs and isomers in biofluids, and would be beneficial for the mechanism studies of related diseases.

96-Well Microtiter Plate Made of Paper: A Printed Chemosensor Array for Quantitative Detection of Saccharides.

Simple, rapid, and accurate detection methods for saccharides are potentially applicable to various fields such as clinical and food chemistry. However, the practical applications of on-site analytical methods are still limited. To this end, herein, we propose a 96-well microtiter plate made of paper as a paper-based chemosensor array device (PCSAD) for the simultaneous classification of 12 saccharides and the quantification of fructose and glucose among 12 saccharides. The mechanism of the saccharide detection relied on an indicator displacement assay (IDA) on the PCSAD using four types of catechol dyes, 3-nitrophenylboronic acid, and the saccharides. The design of the PCSAD and the experimental conditions for the IDA were optimized using a central composite design. The chemosensors exhibited clear color changes upon the addition of saccharides on the paper because of the competitive boronate esterification. The color changes were employed for the subsequent qualitative, semiquantitative, and quantitative analyses using an automated algorithm combined with pattern recognition for digital images. A qualitative linear discrimination analysis offered discrimination of 12 saccharides with a 100% classification rate. The semiquantitative analysis of fructose in the presence of glucose was carried out from the viewpoint of food analysis utilizing a support vector machine, resulting in clear discrimination of the various concentrations of fructose. Most importantly, the quantitative detection of fructose in two types of commercial soft drinks was also successfully carried out without sample pretreatments. Thus, the proposed PCSAD can be a powerful method for on-site food analyses that can meet the increasing demand from consumers for sensors of saccharides.

Simplest Chemosensor Array for Phosphorylated Saccharides.

We believe that "the simpler we are, the more complete we become" is a key concept of chemical sensing systems. In this work, a "turn-on" fluorescence chemosensor array relying on only two self-assembled molecular chemosensors with ability of both qualitative and quantitative detection of phosphorylated saccharides has been developed. The easy-to-prepare chemosensor array was fabricated by in situ mixing of off-the-shelf reagents (esculetin, 4-methylesculetin, and 3-nitrophenylboronic acid). The fluorescence-based saccharide sensing system was carried out using indicator displacement assay accompanied by photoinduced electron transfer (PeT) under various pH conditions. The simultaneous recognition of 14 types of saccharides including glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) was achieved with a successful classification rate of 100%. We also succeeded in the quantitative analysis of a mixture of glucose (Glc), as an original substrate, G6P and F6P, as enzymatic products in pseudoglycolysis pathway. Finally, levels of Glc and F6P in human induced pluripotent stem (hiPS) cells were indirectly monitored by using our proposed chemosensor array. Glc and F6P in supernatants of hiPS cells were classified by linear discriminant analysis as a pattern recognition model and the observed clusters represent the activity of hiPS cells. The results show the high accuracy of the proposed chemosensor array in detection of phosphorylated and similarly modified saccharides.

Boronic Derivatization of Monoacylglycerol and Monitoring in Biofluids.

Monoacylglycerols (MAGs) are active mediators involved in multiple biological processes closely related to the pathological development of diabetes, obesity, and cancers. Sensitive and unambiguous detection of MAGs is thus essential; however, previous methods are both indirect and labor-intensive. Herein, we developed a straightforward approach by derivatization of MAGs with 3-nitrophenylboronic acid (3-NPB) for sensitive and selective analysis in cell lysates, tissues, and serums by mass spectrometry (MS). Reaction occurring between boronic acid and cis-diol moiety of MAGs blocked the formation of multiple adduct ions and tuned MAGs to negatively charged carrying species. In addition, the characteristic isotopic distribution of boron specialized the presence of modified MAGs in MS and led to distinctive identification. To eliminate endogenous interferences, we further introduced isotopic labeled d4-NPB equivalently premixed with d0-NPB to perform MAG derivatization, which resulted in rapid identification of modified MAGs in biofluids by displaying doublet peak characteristics. A comparative quantification approach was thereafter evoluted to reveal the amountvariation of MAGs by d0-NPB and d4-NPB separately derivatized in different pathological tissue and serum samples. The presently developed NPB-based derivatization approach is expected to be essential in the metabolic study of MAG-related diseases.

A Saccharide Chemosensor Array Developed Based on an Indicator Displacement Assay Using a Combination of Commercially Available Reagents.

Herein, a very simple colorimetric chemosensor array is reported for saccharides (D-glucose, D-fructose, D-xylose, D-galactose, D-mannose, L-rhamnose, and N-acetyl-D-gluosamine). While various types of chemosensors for saccharides have been investigated extensively to-this-date, tremendous additional efforts are still required on a regular basis for the syntheses of new chemosensors. Complicated syntheses would be a bottleneck, given that artificial receptor-based chemosensing systems are not so popular in comparison to biomaterial-based (e.g., enzyme-based) sensing systems. Toward this end, chemosensor array systems using molecular self-assembled materials can avoid the abovementioned synthetic efforts and achieve simultaneous qualitative and quantitative detection of a number of guest saccharides. Using a practical approach, we focus on an indicator displacement assay (IDA) to fabricate a chemosensor array for colorimetric saccharide sensing. On this basis, 3-nitrophenylboronic acid (3-NPBA) spontaneously reacts with catechol dyes such as alizarin red S (ARS), bromopyrogallol red (BPR), pyrogallol red (PR), and pyrocatechol violet (PV), and yields boronate ester derivatives with color changes. The addition of saccharides into the aqueous solution of the boronate esters induces color recovery owing to the higher binding affinity of 3-NPBA for saccharides, thus resulting in the release of dyes. By employing this system, we have succeeded in discriminating saccharides qualitatively and quantitatively with a classification success rate of 100%. Most importantly, our chemosensor array has been fabricated by only mixing low cost commercially available reagents in situ, which means that complicated synthetic processes are avoided for saccharide sensing. We believe this simple colorimetric assay that uses only commercially available reagents can create new, user-friendly supramolecular sensing pathways for saccharides.

Boronic acid inhibitors of the class A β-lactamase KPC-2

The rapid rise of antimicrobial resistance is one of the greatest challenges currently facing medical science. The most common cause of resistance to β-lactam antibiotics is the expression of β-lactamase enzymes, such as KPC-2. As such the development of novel inhibitors of KPC-2 and related enzymes is of the upmost importance. We report the design and synthesis of novel boronic acid transition state analogs containing a 1,4-substituted 1,2,3-triazole linker based on the known inhibitor 3-nitrophenyl boronic acid and demonstrate that they are promising scaffolds for the development inhibitors of KPC-2 with the ability to recover sensitivity to the antibiotic cefotaxime.

Colorimetric sensor array–smartphone–remote server coupling system for rapid detection of saccharides in beverages

A kind of “colorimetric sensor array–smartphone–remote server” coupling system was constructed for rapid on-site testing of saccharides. First, the binding capacity between saccharides and boric acid compounds (boric acid, phenylboronic acid and 3-nitrophenylboronic acid) was studied. The binding capacity of 3-nitrophenylboronic acid was found to be the highest, followed by phenylboronic acid and boric acid. Then a small-scale colorimetric sensor array (2 × 2) of pH indicator based on affinity interaction between 3-nitrophenylboronic acid and saccharides was developed to detect 19 kinds of saccharides. A camera phone was used to acquire the array images before and after reaction, then the self-developed color discrimination software in smartphone was applied to process pictures in order to obtain the color difference image and data of analytes. The color difference data were analyzed by several methods, including principal component analysis, hierarchical cluster analysis and linear discriminant analysis. The analysis results showed that the sensor array (2 × 2) established in this paper has great discriminative capability for 19 kinds of saccharides, and the classification accuracy is as high as 100%. Nineteen different quantitative models of saccharides that showed high accuracy and precision were established based on partial least-square method. Finally, the smartphone was connected to a remote server on which the qualitative analysis and quantitative analysis models for analytes had been established. The color difference data obtained by the smartphone were uploaded to the remote server for the qualitative analysis and quantitative analysis of saccharides. The effectiveness of the “colorimetric sensor array–smartphone–remote server” coupling system in rapid on-site detection of saccharides was further verified by the spike and recovery experiments. The qualitative analysis results showed that this coupling system could distinguish all of the analytes without a mistake, and the quantitative analysis results showed that the predicted values for saccharides were close to the real values.

Hexafluoro-2-propanol-assisted quick and chemoselective nitro reduction using iron powder as catalyst under mild conditions

Hexafluoro-2-propanol as the promoter for the quick nitro reduction using a combination of iron powder and 2N HCl aqueous solution is reported. This methodology has several positive features, as it is of room temperature, remarkably short reaction time. A wide range of substrates including those bearing reducible functional groups such as aldehyde, ketone, acid, ester, amide, nitrile, halogens, even allyl, propargyl and heterocycles are chemoselectively reduced in good to excellent yields, even on gram scale. Notably, the highly selective reduction of 3-nitrophenylboronic acid is achieved quantitatively. The reduction is also tolerant of common protecting groups, and aliphatic nitro compound, 1-nitrooctane can be reduced successfully.

A molecular self-assembled colourimetric chemosensor array for simultaneous detection of metal ions in water.

We propose a novel strategy for a high-throughput sensing of metal ions using a molecular self-assembled colourimetric chemosensor array. The proposed colourimetric assay has been achieved by only using the combination of commercially available materials. Importantly, the easy-to-prepare assay can be utilised to quantitatively detect metal ions under competitive conditions.

Nanoparticle-enhanced fluorescence emission for non-separation assays of carbohydrates using a boronic acid-alizarin complex.

Addition of crosslinked polymer nanoparticles into a solution of a 3-nitrophenylboronic acid-alizarin complex leads to significant enhancement of fluorescence emission. Using the nanoparticle-enhanced boronic acid-alizarin system has improved greatly the sensitivity and extended the dynamic range of separation-free fluorescence assays for carbohydrates.

Brønsted versus Lewis Acid Type Anion Recognition by Arylboronic Acids.

Interactions between arylboronic acids and a series of anions as tetrabutylammonium salts in DMSO and MeCN were studied by (1)H and (11)B NMR as well as spectrophotometrically. Boronic acids act as Brønsted acid type receptors through hydrogen bonding with B(OH)2 hydroxyl groups toward Cl(-), Br(-), HSO4(-), and AcO(-), but they act as Lewis acid type receptors toward F(-) and H2PO4(-), which form tetrahedral adducts with the B(III) center of boronic acids, although there is also evidence for some contribution of hydrogen bonding with these anions. The Hammett plot for the binding constants of AcO(-) with 3- and 4-substituted phenylboronic acids in DMSO is nonlinear, with a small negative slope for electron-donating and weakly electron-accepting substituents and a large positive slope for strongly electron-accepting substituents. 3-Nitrophenylboronic acid recognizes zwitterions of amino acids in DMSO, and its UV absorption maximum undergoes a significant red shift in the presence of acetate anions, providing a means for sensing anions optically. Arylboronic acids as Brønsted acid type receptors show relatively low sensitivity to solvent polarity and are equally or even more efficient than widely employed proton donors such as ureas or dicarboxamides.

Universal reaction mechanism of boronic acids with diols in aqueous solution: kinetics and the basic concept of a conditional formation constant.

To establish a detailed reaction mechanism for the condensation between a boronic acid, RB(OH)2, and a diol, H2L, in aqueous solution, the acid dissociation constants (Ka(BL)) of boronic acid diol esters (HBLs) were determined based on the well-established concept of conditional formation constants of metal complexes. The pKa values of HBLs were 2.30, 2.77, and 2.00 for the reaction systems, 2,4-difluorophenylboronic acid and chromotropic acid, 3-nitrophenylboronic acid and alizarin red S, and phenylboronic acid and alizarin red S, respectively. A general and precise reaction mechanism of RB(OH)2 with H2L in aqueous solution, which can serve as a universal reaction mechanism for RB(OH)2 and H2L, was proposed on the basis of (a) the relative kinetic reactivities of the RB(OH)2 and its conjugate base, that is, the boronate ion, toward H2L, and (b) the determined pKa values of HBLs. The use of the conditional formation constant, K', based on the main reaction: RB(OH)2 + H2L (K1)⇌ RB(L)(OH)(-) + H3O(+) instead of the binding constant has been proposed for the general reaction of uncomplexed boronic acid species (B') with uncomplexed diol species (L') to form boronic acid diol complex species (esters, BL') in aqueous solution at pH 5-11: B' + L' (K')⇌ BL'. The proposed reaction mechanism explains perfectly the formation of boronic acid diol ester in aqueous solution.

ChemInform Abstract: 3,5‐Bis(pentafluorosulfanyl)phenylboronic Acid: A New Organocatalyst for Conia‐ene Carbocyclization of 1,3‐Dicarbonyl Compounds Having Terminal Alkynes.

Abstract 3,5-Bis(pentafluorosulfanyl)phenylboronic acid 1 was introduced as an efficient organocatalyst for Conia-ene carbocyclization of 1,3-dicarbonyl compounds having terminal alkynes. A variety of 2-alkynic 1,3-dicarbonyl compounds were smoothly converted to ene-carbocyclization products in moderate to excellent yields. Compared with the reported catalyst, 3-nitro phenylboronic acid, catalyst 1 is slightly better in a non-polar solvent such as toluene and Solkane ® 365mfc (1,1,1,3,3-pentafluorobutane). These results indicate that the SF 5 function can be a lipophilic and sterically demanding alternative to the NO 2 group in catalyst design.

A facile one-pot synthesis of dicycloalkenopyridines at ambient temperature conditions

An efficient synthesis of dicycloalkenopyridines was achieved via one-pot three-component condensation of aromatic aldehyde, cyclohexanone, and hydroxylamine hydrochloride using 3-nitrophenylboronic acid as an efficient catalyst under ambient condition. The current methodology offers several advantages such as high yields (78–90%) and simple experimental work-up at ambient temperature conditions.

3-Nitrophenylboronic acid-catalyzed efficient one-pot synthesis of 1,4-dihydropyridines and polyhydroquinolines

An efficient protocol for the synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via multi-component coupling reaction of aldehyde, -keto ester and ammonium acetate at room temperature condition using 3-nitrophenylboronic acid as a catalyst is described.

3,5-Bis(pentafluorosulfanyl)phenylboronic acid: A new organocatalyst for Conia-ene carbocyclization of 1,3-dicarbonyl compounds having terminal alkynes

3,5-Bis(pentafluorosulfanyl)phenylboronic acid 1 was introduced as an efficient organocatalyst for Conia-ene carbocyclization of 1,3-dicarbonyl compounds having terminal alkynes. A variety of 2-alkynic 1,3-dicarbonyl compounds were smoothly converted to ene-carbocyclization products in moderate to excellent yields. Compared with the reported catalyst, 3-nitro phenylboronic acid, catalyst 1 is slightly better in a non-polar solvent such as toluene and Solkane®365mfc (1,1,1,3,3-pentafluorobutane). These results indicate that the SF5 function can be a lipophilic and sterically demanding alternative to the NO2 group in catalyst design.

Crystal Structures of KPC-2 β-Lactamase in Complex with 3-Nitrophenyl Boronic Acid and the Penam Sulfone PSR-3-226

Class A carbapenemases are a major threat to the potency of carbapenem antibiotics. A widespread carbapenemase, KPC-2, is not easily inhibited by β-lactamase inhibitors (i.e., clavulanic acid, sulbactam, and tazobactam). To explore different mechanisms of inhibition of KPC-2, we determined the crystal structures of KPC-2 with two β-lactamase inhibitors that follow different inactivation pathways and kinetics. The first complex is that of a small boronic acid compound, 3-nitrophenyl boronic acid (3-NPBA), bound to KPC-2 with 1.62-Å resolution. 3-NPBA demonstrated a K(m) value of 1.0 ± 0.1 μM (mean ± standard error) for KPC-2 and blocks the active site by making a reversible covalent interaction with the catalytic S70 residue. The two boron hydroxyl atoms of 3-NPBA are positioned in the oxyanion hole and the deacylation water pocket, respectively. In addition, the aromatic ring of 3-NPBA provides an edge-to-face interaction with W105 in the active site. The structure of KPC-2 with the penam sulfone PSR-3-226 was determined at 1.26-Å resolution. PSR-3-226 displayed a K(m) value of 3.8 ± 0.4 μM for KPC-2, and the inactivation rate constant (k(inact)) was 0.034 ± 0.003 s(-1). When covalently bound to S70, PSR-3-226 forms a trans-enamine intermediate in the KPC-2 active site. The predominant active site interactions are generated via the carbonyl oxygen, which resides in the oxyanion hole, and the carboxyl moiety of PSR-3-226, which interacts with N132, N170, and E166. 3-NPBA and PSR-3-226 are the first β-lactamase inhibitors to be trapped as an acyl-enzyme complex with KPC-2. The structural and inhibitory insights gained here could aid in the design of potent KPC-2 inhibitors.

Direct analysis of polyols using 3-nitrophenylboronic acid in capillary electrophoresis: thermodynamic and electrokinetic principles of molecular recognition

The design of boronic acid sensors for photometric detection of carbohydrates has relied on exploiting differences in the thermodynamic stability of complex formation for molecular recognition. Herein, we introduce a direct method for analysis of sugar alcohols using 3-nitrophenylboronic acid (NPBA) as an electrokinetic probe in capillary electrophoresis (CE). Dynamic complexation of neutral polyols by NPBA during electromigration allows for their simultaneous resolution and UV detection based on formation of an anionic ternary boronate ester complex in phosphate buffer. Unlike conventional boronic acid sensors, thermodynamic and electrokinetic processes in CE allow for improved selectivity for the resolution of sugar alcohol stereoisomers having different vicinal polyol chain lengths even in cases when binding affinity is similar due to differences in their complex mobility. Three complementary approaches were investigated to compare the thermodynamics of polyol chelation with NPBA, namely direct binding assays by CE, UV absorbance spectroscopy and an indirect pK (a) depression method. Overall, CE offers a convenient platform for characterization of reversible arylboronic acid interactions in free solution while allowing for direct analysis of complex mixtures of neutral/UV-transparent polyols without complicated sample handling.