Boronic Acid Derivatives Research Articles

Investigation of interaction between boronic acids and sugar: effect of structural change of sugars on binding affinity using steady state and time resolved fluorescence spectroscopy and molecular docking

Binding interactions of boronic acid derivatives viz. 2-Methylphenylboronic acid (B1) and 3-Methoxyphenylboronic acid (B2) with mono saccharides (arabinose, fructose and galactose) and disaccharides (sucrose, lactose and maltose) in aqueous condition at pH 7.4 by means of fluorescence spectroscopy is reported in the present investigation. Sugar sensing as well as continuous glucose monitoring (CGM) plays a significant role in diabetes regulation. Sugar sensors mediated through enzymes have their own drawbacks, which led to encouragement to search for designing new sensors through alternate approaches. Among many, fluorescence-based sensors are drawing more attention. Boronic acid-based fluorescence sensors have the capacity to bind reversibly with diols, which makes their demand high in applications. Addition of sugar reduces fluorescence intensities. Change in intensities is associated to cleavage of intermolecular hydrogen bonding which leads in reduced stability of boronate ester. Lineweaver-Burk and Benesi-Hildebrand equation is used for analysing data. Mono sugars are estimated to have higher binding constants. Mutarotation leads to structural changes in saccharides which play a key role in binding interactions. Sugars in furanose form are found to be highly favoured for binding. Molecular docking of B1 and B2 with proteins with PDB ID: 2IPL and 2IPM being periplasmic was done with the help of Schrodinger Maestro 11.2 version. GLIDE scores terms are used for expressing binding affinity.

Magnetic bead-based electrochemical and colorimetric methods for the detection of poly(ADP-ribose) polymerase-1 with boronic acid derivatives as the signal probes

Poly(ADP-ribose) polymerase-1 (PARP-1), as a highly conserved nuclear enzyme, can catalyze the transfer of multiple ADP-ribose units from β-nicotinamide adenine dinucleotide (NAD+) to substrate proteins, including PARP-1 itself. In this work, two boronic acid derivatives, ferroceneboronic acid (FcBA) and 4-mercaptophenylboronic acid (MPBA) were used as the signal probes for electrochemical and colorimetric detection of PARP-1, respectively. The detection platform was constructed by modification of double-stranded DNA (dsDNA) on the surface of magnetic beads (MBs). Once PARP-1 was captured by the MB-dsDNA, auto-PARylation was initiated and the PAR products consisting of abundant ribose units were covalently bound to FcBA or MPBA through the formation of boronate ester covalent bonds. Sequestration of FcBA or MPBA by the PAR-covered MBs led to the decrease in the electrochemical signal of FcBA or preventing the MPBA-triggered aggregation of gold nanoparticle indicators. The change of oxidation current or adsorption intensity (color) was dependent upon the concentration and activity of PARP-1. A wide linear range of 0.1 ∼ 50 U was obtained for the electrochemical or colorimetric assays. The methods have been used to evaluate the inhibition efficiency and monitor the PARP-1 activity in living and apoptotic cancer cells.

Magnetic bead-based electrochemical and colorimetric assays of circulating tumor cells with boronic acid derivatives as the recognition elements and signal probes

Simple, sensitive and rapid detection of circulating tumor cells (CTCs) is of great importance for early diagnosis and therapy of cancers. Overexpression of sugar units on cell surface is related to the phenotypes of many cancers. Based on the boronate ester interaction, we reported the electrochemical and colorimetric detection of CTCs with high simplicity and sensitivity. Specifically, ferroceneboronic acid (FcBA) can be measured by differential pulse voltammetry and 4-mercaptophenylboronic acid (MPBA) can induce the aggregation and color change of gold nanoparticles (AuNPs). CTCs captured by the aptamer-modified magnetic beads (Apt-MBs) can sequestrate FcBA or MPBA molecules by the formation of boronate ester bonds, thus leading to the decrease in the electrochemical signal of FcBA or preventing the MPBA-triggered aggregation of AuNPs. Due to the overexpression of sugar groups on the surface of CTCs, the amplification-free methods exhibited high sensitivity and obviated the use of additional antibody or aptamer for the recognition of captured cells. With MCF-7 cancer cell as the model, 50 cells can be readily determined by the electrochemical and colorimetric methods. The proposed strategy is valuable for probing of cell glycosylation and designing of novel sensing devices for detection of sugar-containing biological macromolecules and cells.

Binding Interaction Between Boronic Acid Derivatives with Monosaccharaides: Effect of Structural Change of Monosaccharaides Upon Binding Using S–V Plots

AbstractSugar sensing and continuous monitoring of glucose (CGM) play an important and vital role in controlling diabetes. The present enzyme‐based sugar sensors have their own drawbacks. Problems associated with them have encouraged alternate approaches to design new sensors. Among many, fluorescent intensity change based sensors are drawing more attention. Fluorescence sensors based on boronic acid derivatives are more popular because of their ability to reversibly bind diol‐containing compounds. Here, the binding ability of two boronic acid derivatives, namely 2‐methylphenyl boronic acid (B1) and 3‐methoxyphenyl boronic acid (B2) with mono saccharides (sugars), is under investigation. The sugar concentration is kept nearly 1000 times more than that of boronic acid. The interactions of B1 and B2 with three saccharides (d‐sorbitol, dextrose, and fructose) are studied by absorbance and steady‐state fluorescence. Both B1 and B2 fluorescence is quenched by formation of esters with saccharides. The results of absorbance and fluorescence measurements indicate that the studied sugars can be ordered by their affinity to B1 as: d‐sorbitol > xylose > dextrose and for B2 as: dextrose > xylose > d‐sorbitol. In each case, slope of modified S–V plots is nearly one indicating only a single binding site in boronic acids for sugars.

Core-shell iron oxide@cathecol-polymer@palladium/copper nanocomposites as efficient and sustainable catalysts in cross-coupling reactions

Magnetic core-shell Fe2O3@polymer-Pd/Cu nanocomposites (NCs) were developed as efficient and sustainable nanocatalysts for cross-coupling reactions. The designed NCs consisted of three components: i) a magnetic core (Fe2O3 nanoparticle), which allowed the recovery and reuse of the NCs, enhancing thus their attractiveness as green catalysts; ii) a catechol-based polymer coating, chosen because of its strong chelating ability towards metal ions, and its potential to be obtained from biomass (lignin depolymerization); and iii) catalytically active metal nanoparticles (Pd and Cu NPs) immobilized via in situ formation onto the polymeric shell. As-prepared Pd-based NCs successfully catalyzed Suzuki-Miyaura cross-coupling reactions, achieving yields between 87% and 97% in only 20–40 min depending on the aryl halides and boronic acid derivatives. Similarly, Cu-based NCs exhibited a quite good catalytic efficiency (> 80%) in the synthesis of propargylamines via A3 coupling reaction of phenylacetylene with various aldehydes and amines. Importantly, these NCs presented a good reusability, without significant decrease in efficiency after several cycles. However, the major advantage of the designed NCs is the lower Pd or Cu content (1.5 wt% and 2.6 wt%, respectively) as compared to most of the reported similar catalysts (between 3 – 6 wt% for Pd and > 5 wt% for Cu), which is a key challenge in view of developing cost-effective and environment-friendly catalysts while maintaining a high efficiency.

In Situ‐Forming Glucose‐Responsive Hydrogel from Hyaluronic Acid Modified with a Boronic Acid Derivative

AbstractHydrogels are a promising class of biomaterials for sustained drug release applications. The use of covalently cross‐linked hydrogels for drug delivery applications may be limited due to their manufacturing complexity and the high injection forces required for their administration. Stimulus‐responsive hydrogels, which are engineered to respond to stimuli such as pH, temperature, ionic strength, or chemical potential, may overcome these shortcomings and enable the development of injectable hydrogels. This study presents a strategy for forming hydrogels such that a sol–gel transition occurs in response to physiologically relevant glucose concentrations. A hyaluronic acid (HA) polymer backbone is modified with 3‐aminophenylboronic acid, which is able to reversibly bind glucose with a 2:1 stoichiometry. The boronic acid‐functionalized polymer is demonstrated to be glucose responsive, as indicated by its spontaneous hydrogelation and subsequent increase in stiffness as a function of glucose concentration. Furthermore, the transient nature of the boronic acid‐glucose cross‐linking enables the hydrogel to self‐heal after physical rupture. A proof‐of‐concept gelation in alkaline conditions is demonstrated, but the system may be adapted for gelation at physiological pH using modified boronic acids. These HA–boronic acid conjugates have potential utility as in situ‐forming hydrogels for sustained drug release applications.

Novel Phenothiazine-Bridged Porphyrin-(Hetero)aryl dyads: Synthesis, Optical Properties, In Vitro Cytotoxicity and Staining of Human Ovarian Tumor Cell Lines.

We report here the synthetic procedure applied for the preparation of new AB3-type and trans-A2B2 type meso-halogenophenothiazinyl-phenyl-porphyrin derivatives, their metal core complexation and their peripheral modification using Suzuki–Miyaura cross coupling reactions with various (hetero)aryl (phenothiazinyl, 7-formyl-phenothiazinyl, (9-carbazolyl)-phenyl and 4-formyl-phenyl, phenyl) boronic acid derivatives. The meso-phenothiazinyl-phenyl-porphyrin (MPP) dyes family was thus extended by a series of novel phenothiazine-bridged porphyrin-(hetero)aryl dyads characterized by UV–Vis absorption/emission properties typical to the porphyrin chromophore, slightly modulated by increasing the size of peripheral substituents. Three phenothiazine-bridged porphyrin-heteroaryl dyads with fluorescence emission above 655 nm were selected as fluorophores in red spectral region for applications in cellular staining of human ovarian tumors. In vitro experiments of cell metabolic activity displayed a moderate toxicity on human ovarian tumor cell lines (OVCAR-3, cisplatin-sensitive A2780 and cisplatin-resistant A2780cis respectively). Visualization of the stained living cells was performed both by fluorescence microscopy imaging and by fluorescence lifetime imaging under two photon excitation (TPE-FLIM), confirming their cellular uptake and the capability of staining the cell nucleus.

N-Nitroheterocycles: Bench-Stable Organic Reagents for Catalytic Ipso-Nitration of Aryl- and Heteroarylboronic Acids.

Photocatalytic and metal-free protocols to access various aromatic and heteroaromatic nitro compounds through ipso-nitration of readily available boronic acid derivatives were developed using non-metal-based, bench-stable, and recyclable nitrating reagents. These methods are operationally simple, mild, regioselective, and possess excellent functional group compatibility, delivering desired products in up to 99% yield.

Facile and Versatile Synthesis of End‐Functionalized Poly(phenylacetylene)s: A Multicomponent Catalytic System for Well‐Controlled Living Polymerization of Phenylacetylenes

AbstractA rhodium‐based multicomponent catalytic system for well‐controlled living polymerization of phenylacetylenes has been developed. The catalytic system is composed of readily available and bench‐stable [Rh(nbd)Cl]2, aryl boronic acid derivatives, diphenylacetylene, 50 % aqueous KOH, and PPh3. This system offers a method for the facile and versatile synthesis of various end‐functionalized cis‐stereoregular poly(phenylacetylene)s because components from aryl boronic acids and diphenylacetylene were introduced to the initiating end of the polymers. The polymerization reaction shows a typical living nature with a high initiation efficiency, and the molecular weight of the resulting poly(phenylacetylene)s can be readily controlled with very narrow molecular‐weight distributions (Mw/Mn=1.02–1.09). The experimental results suggest that the present catalytic system has a higher polymerization activity than the polymerization activities of other rhodium‐based catalytic systems previously reported.

Facile and Versatile Synthesis of End-Functionalized Poly(phenylacetylene)s: A Multicomponent Catalytic System for Well-Controlled Living Polymerization of Phenylacetylenes.

A rhodium-based multicomponent catalytic system for well-controlled living polymerization of phenylacetylenes has been developed. The catalytic system is composed of readily available and bench-stable [Rh(nbd)Cl]2 , aryl boronic acid derivatives, diphenylacetylene, 50 % aqueous KOH, and PPh3 . This system offers a method for the facile and versatile synthesis of various end-functionalized cis-stereoregular poly(phenylacetylene)s because components from aryl boronic acids and diphenylacetylene were introduced to the initiating end of the polymers. The polymerization reaction shows a typical living nature with a high initiation efficiency, and the molecular weight of the resulting poly(phenylacetylene)s can be readily controlled with very narrow molecular-weight distributions (Mw /Mn =1.02-1.09). The experimental results suggest that the present catalytic system has a higher polymerization activity than the polymerization activities of other rhodium-based catalytic systems previously reported.

Smoke Hazard Assessment of Cypress Wood Coated with Boron/Silicon Sol Compounds

In this study, boron/silicon sol compounds were applied to wood for construction and durable materials, and fire risks were investigated in terms of smoke performance index (SPI), smoke growth index (SGI), and smoke intensity (SI). The compound was synthesized by reacting tetraethoxyorthosilicate with boric acid and boronic acid derivatives. Smoke characteristics were investigated using a cone calorimeter (ISO 5660-1) equipment for cypress wood. The fire intensity fixed the external heat flux at 50 kW/m<sup>2</sup>. The smoke performance index measured after the combustion reaction increased between 13.4% and 126.7% compared with cypress wood. The fire risk due to the smoke performance index decreased in the order of cypress, phenylboronic acid/silicon sol (PBA/Si), (2-methylpropyl) boronic acid/silicon sol (IBBA/Si), boric acid/silicon sol (BA/Si). The smoke growth index decreased between 12.0% and 57.5% compared to the base specimen. The risk of fire caused by the smoke growth index decreased in the order of cypress, PBA/Si, IBBA/Si, BA/Si. The fire risk due to smoke intensity decreased between 3.2% and 57.8%, and in the order of cypress, PBA/Si, IBBA/Si, BA/Si. CO<sub>peak</sub> concentrations ranged between 85 and 93 ppm, and decreased between 37% and 43% compared to the base specimen. A comprehensive assessment of the fire risk on smoke hazards decreased in the order of cypress, PBA/Si, IBBA/Si, BA/Si.

Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies.

Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.

Catalytic asymmetric hydrogenation of (Z)-α-dehydroamido boronate esters: direct route to alkyl-substituted α-amidoboronic esters.

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized. Using this approach, a class of therapeutically relevant alkyl-substituted α-amidoboronic esters was easily synthesized in high yields with generally excellent enantioselectivities (up to 99% yield and 99% ee). The utility of the products has been demonstrated by transformation to their corresponding boronic acid derivatives by a Pd-catalyzed borylation reaction and an efficient synthesis of a potential intermediate of bortezomib. The clean, atom-economic and environment friendly nature of this catalytic asymmetric hydrogenation process would make this approach a new alternative for the production of alkyl-substituted α-amidoboronic esters of great potential in the area of organic synthesis and medicinal chemistry.

Synthesis, Characterization and Antimicrobial Activities of Pentacyclic Oxadiazadiborinanes

In this study we have expanded upon a family of substituted pentacyclic oxadiazadiborinane derivatives from the condensation of carbohydrazide with ortho-formylphenyl boronic acid derivatives containing a variety of chemical and physical properties. All new complexes have been characterized fully including two single crystal X-ray diffraction studies which confirm the solid-state structure of these species along with an unusual methanol activation product, which appears to be a minor solid-state side product. The lack of inherent solubility of these compounds in common physiological media precluded us from doing traditional antimicrobial activities. To circumvent this problem, we incorporated these boron compounds into chitosan films. Only weak or moderate activities against Gram-negative and Gram-positive bacteria were observed in this study.

Suzuki-Miyaura Çapraz Eşleşme Reaksiyonunda Katalizör Olarak Heterosiklik Bileşiklerin Uygulanması

Four different benzimidazolium salts (1-4) were prepared in three steps at 80 oC and their structures were elucidated using spectroscopic methods. The compounds (1-4) obtained were tested in in situ medium as catalyst in the carbon-carbon (C-C) bond formation reactions of two different boronic acid derivatives with various aryl halides in the presence of palladium acetate (PdOAc)2 and sodium tertiarybutoxide (NaOBut) as a base. With this reaction, four coupling products (5-8) were synthesized in different yields ranging from 11 to 93%. Compound 2 from the carbene precursors tested in the Suzuki-Miyaura cross-coupling reaction was found to be a more effective catalyst candidate than others.

Tunable Synthesis of α-Amino Boronic Esters from Available Aldehydes and Amines through Sequential One-Pot Dehydration and Copper-Catalyzed Borylacylation.

Copper-catalyzed multicomponent borylacylation of imines with acid chlorides and bis(pinacolato)diboron was developed for the preparation of synthetically useful and pharmacologically relevant α-amino boronic acid derivatives. Starting from a range of acid chlorides and imines with aryl, heteroaryl, and alkyl substituents, most of these ligand-free reactions proceeded smoothly at room temperature in moderate to good yields. Furthermore, a facile and convenient one-pot, multistep access to the direct synthesis of α-amino boronic acid derivatives from available aldehydes and amines was also developed.

A novel fluorescent glycopolymer for endogenous hydrogen peroxide imaging in living cells in a fully aqueous environment

The development of H2O2-responsive fluorescent glycopolymers with high specificity, sensitivity, and water solubility is a promising strategy for developing probes to detect the production and delivery of endogenous H2O2. Herein, two series of fluorescent glycopolymers (boronic acid derivatives, PG-PFE, and borate derivatives, PG-PFW) were synthesized through esterification and the Williamson reaction, respectively. To increase the sensitivity of the fluorescent glycopolymers, the effect of the reaction conditions on the grafting ratio was investigated in detail. Compared with the PG-PFE samples, the PG-PFW samples had a higher grafting ratio due to the highly efficient Williamson reaction. The structure and properties of the fluorescent glycopolymers were characterized by using nuclear magnetic resonance spectroscopy, gel permeation chromatography, ultraviolet spectroscopy, and photoluminescent spectroscopy. The obtained results showed that all of these fluorescent glycopolymers had good water solubility, low cytotoxicity, and selective responsiveness toward H2O2. HPG-PFW-5, with the highest grafting ratio, displayed a higher sensitivity toward H2O2 and higher stability during hydrolysis than the other materials. In confocal laser scanning microscope images, all of the fluorescent glycopolymers were observed only in cellular mitochondria, and HPG-PFW-5 exhibited a high degree of overlap with Mitotracker Red because of its high sensitivity. Two series of fluorescent glycopolymers (boronic acid derivatives, PG-PFE, and borate derivatives, PG-PFW) were synthesized through different methods. Compared with the PG-PFE samples, the PG-PFW samples had a higher grafting ratio due to the highly efficient Williamson reaction. The fluorescent glycopolymers possessed good water solubility, low cytotoxicity and selective responsiveness toward H2O2. Meantime, the fluorescent glycopolymers were imaged only in cellular mitochondria based on the fact that endogenous H2O2 is mainly distributed in cellular mitochondria.

HbA1c detection via high-sensitive boronate based surface plasmon resonance sensor

Glycosylated Hemoglobin, known as HbA1c, is the most commonly used molecule to track and diagnose the Type II diabetes and gives very convincing accurate results. Tracking the HbA1c is also an early diagnostic tool to indicate diabetes occurrence in high risk patience. Glycosylated hemoglobin is the result of glucose binding of the β-chain of hemoglobin to N-terminal valine and reflects the average glucose value over the past 2–3 months. HbA1c in the blood concentration of more than 141 mg/dL is often enough to diagnose diabetes. Boronic acid derivatives are often used in HbA1c determination due to the carbohydrate relationship based on the cis-diol interaction and determinations based on this association are mostly carried out by enzymatic sensors and HPLC. In addition to these methods, sensor studies have also started to be developed as an alternative. In this study, it is aimed to determine HbA1c by a surface plasmon resonance sensor (SPR) modified with a boronic acid derivative vinyl phenyl boronic acid. This study is shown that the pH value is an important parameter for binding and the signal received is increased as the concentration increases. Even at low concentrations like 10 μg/mL, signal can be received and it implies that more accurate measurement can be made at clinical concentration values which are higher. In artificial plasma studies, different sensograms are obtained for human serum albumin, immunoglobulin G, and hemoglobin molecules which all could bind to modified chip and the selectivity to the molecules are distinctively differentiated in comparison with HbA1c.

Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme

Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX.

Interface modification of DNTT-based organic field effect transistors using boronic acid derivatives

The dielectric/semiconductor interface in organic field effect transistors (OFETs) is critical to their performance. Modification of this interface with functional molecules provides a wide range of possibilities for their applications as sensors. In this work, boronic acid molecules were used to modify the SiO2 dielectric surface in dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene based OFETs. The device parameters, including most notably the threshold voltage, were significantly improved. The dielectric/semiconductor interface was analyzed using various measurement techniques, such as contact angle and atomic force microscopy. Our work provides evidence that easily functionable boronic acid derivatives improve the device performance of OFETs, which lays the foundation for further studies of such interface modified OFETs for use in sensing applications.