Phenylboronic Acid Derivatives Research Articles

Triazole-substituted phenylboronic acids as tunable lead inhibitors of KPC-2 antibiotic resistance

Inhibition of β-lactamases is a promising strategy to overcome antimicrobial resistance to commonly used β-lactam antibiotics. Boronic acid derivatives have proven to be effective inhibitors of β-lactamases due to their direct interaction with the catalytic site of these enzymes. We synthesized a series of phenylboronic acid derivatives and evaluated their structure-activity relationships as Klebsiella pneumoniae carbapenemase (KPC-2) inhibitors. We identified potent KPC-2 inhibitors 2e &6c (Ki = 0.032 μM and 0.038 μM, respectively) that enhance the activity of cefotaxime in KPC-2 expressing Escherichia coli. The measured acid dissociation constants (pKa) of selected triazole-containing phenylboronic acids was broad (5.98–10.0), suggesting that this is an additional property of the compounds that could be tuned to optimize the target interaction and/or the physicochemical properties of the compounds. These findings will help to guide the future development of boronic acid compounds as inhibitors of KPC-2 and other target proteins.

The interaction between phenylboronic acid derivatives and active ingredients with diphenol structure of traditional Chinese medicine

Many active ingredients of traditional Chinese medicine with important pharmacological effects always have glycol or diphenol structure, which lays a foundation for the combination with phenylboronic acid (PBA) derivatives to form cyclic boronic esters compounds. Herein, four important pharmacological active ingredients, namely baicalein, baicalin, gallic acid and protocatechuic acid, were chosen to study the interaction with PBA derivatives. Five PBA derivatives of 3-aminophenylboronic acid monohydrate (APBA), 3-acrylaminophenylboronic acid (AAPBA), poly(3-acrylaminophenylboronic acid) (PAAPBA), poly([poly(ethylene glycol) methacrylate-block-3-acrylaminophenylboronic acid]) (PEbPB), and poly[poly(ethylene glycol) methacrylate-random-3-acrylaminophenylboronic acid] (PErPB) were used. The interactions between five PBA derivatives and four active ingredients were explored by fluorescent spectrophotometer using the alizarin red (ARS) method. The fluorescent intensity of PBA derivative-ARS-active ingredient mixture was decreasing with the increasing concentrations of active ingredients. In comparison, the fluorescent intensity of PAAPBA, PEbPB, and PErPB showed an obviously decrease after active ingredients were added, while the fluorescent intensity of APBA and AAPBA showed a gradually decrease after active ingredients were added. These results indicated a stronger interaction between PBA polymers and active ingredients than that of APBA and AAPBA. Simultaneously, PEbPB and PErPB could enhance cellular uptake of baicalin in A549 cells. This research provided new strategies for improving the bioavailability and water solubility, extending the circulation time, and wider application of the active ingredients of traditional Chinese medicine in the prevention and therapy of diseases.

Synthetic, spectroscopic, and computational investigations of readily accessible 2‐phenyl‐3‐alkylbenzoxazaboroles

AbstractWe report several new benzoxazaboroles using 2‐aminophenol or 2‐(alkylamino)phenols and phenylboronic acid derivatives. Bis(benzoxazaborole)s were also synthesized using aminophenols and diboronic acids. Characterization of benzoxazaboroles and bis(benzoxazaborole)s was carried out using 1H NMR, 13C NMR, UV–visible, and fluorescence spectroscopic methods along with mass spectrometry and X‐ray crystallography for structural identification. Computational calculations of benzoxazaboroles and bis(benzoxazaborole)s were utilized to support and add to the experimental results. This includes calculations of conformational energies, bond lengths, HOMO‐LUMO energies, and electrostatic potential maps.

Determination of the Influence of Various Factors on the Character of Surface Functionalization of Copper(I) and Copper(II) Oxide Nanosensors with Phenylboronic Acid Derivatives.

In this work, we attempt to determine the influence of the oxidation state of copper [Cu(I) vs Cu(II)], the nature of the interface (solid/aqueous vs solid/air), the incubation time, and the structure of N-substituted phenylboronic acids (PBAs) functionalizing the surface of copper oxide nanostructures (NSs) on the mode of adsorption. For this purpose, 4-[(N-anilino)(phosphono)-S-methyl]phenylboronic acid (1-PBA) and its two analogues (2-PBA and bis{1-PBA}) and the copper oxide NSs were synthesized in a surfactant-/ion-free solution via a synthetic route that allows controlling the size and morphology of NSs. The NSs were characterized by scanning electron microscopy, ultraviolet–visible spectroscopy, Raman spectroscopy, and X-ray diffraction, which confirmed the formation of spherical Cu2O nanoparticles (Cu2ONPs) with a size of 1.5 μm to 600 nm crystallized in a cubic cuprite structure and leaf-like CuO nanostructures (CuONSs) with dimensions of 80–180 nm in width and 400–700 nm in length and crystallized in a monoclinic structure. PBA analogues were deposited on the surface of the copper oxide NSs, and adsorption was investigated using surface-enhanced Raman spectroscopy (SERS). The changes in the orientation of the molecule relative to the substrate surface caused by the abovementioned factors were described, and the signal enhancement on the copper oxide NSs was determined. This is the first study using vibrational spectroscopy for these compounds.

Palladium nanoparticles encapsulated in polyimide nanofibers: An efficient and recyclable catalyst for coupling reaction

In this study, palladium‐encapsulated poly(amic acid) (Pd@PAA) nanofibers were prepared by electrospinning, followed by thermal imidization to synthesize palladium‐encapsulated polyimide (Pd@PI) nanofibers. Scanning electron microscopy (SEM) images confirmed the preparation of uniform and smooth Pd@PAA and Pd@PI nanofibers. Thermogravimetric analysis (TGA) results reveal that the Pd@PI nanofibers possessed excellent thermal stability. The dispersion of palladium nanoparticles in the polyimide nanofibers was characterized by transmission electron microscopy (TEM) and X‐ray diffraction (XRD). The catalysis results show that this Pd@PI fibrous catalyst was very efficient to catalyze the cross‐coupling reactions of aromatic iodides with n‐butyl acrylate (Heck reaction) or phenylboronic acid derivatives (Suzuki reaction) to afford the desired products in good to excellent yields. Moreover, the Pd@PI catalyst could be easily separated and recovered from the reaction mixture by simple filtration due to the regular fibrous structure and reused for 10 times for both Heck and Suzuki reactions without obvious loss of its initial catalytic activity. Thus, the Pd@PI nanofiber catalyst holds great potential in chemical industry in terms of its excellent catalytic activity and stability.

Synthesis, crystal structures and catalytic activities of palladium complexes with coumarin-functionalised N-heterocyclic carbene ligands

In this contribution, we synthesized five new coumarin-functionalised PEPPSI type Pd-NHC complexes in order to examine their catalyst properties. The complexes were synthesized by the reaction of PdCl2 and corresponding benzimidazolium chloride in pyridine in the presence of excess amount of K2CO3. The structures of complexes were fully characterised using NMR and IR spectroscopy, elemental analyses and X-ray diffraction analyses. Crystal structures of four complexes revealed that they have slightly distorted square-planar geometry. Catalytic activities of complexes were tested in Suzuki-Miyaura reaction of phenylboronic acid and aryl bromide derivatives in H2O-DMF solvent system.

Multinuclear NMR Study on the Formation and Polyol-Induced Deformation Mechanisms of Wormlike Micelles Composed of Cetyltrimethylammonium Bromide and 3-Fluorophenylboronic Acid.

We had previously confirmed a glucose-responsive decrease in the viscosity of cetyltrimethylammonium bromide (CTAB) and phenylboronic acid (PBA) wormlike micelle (WLM) systems. However, the mechanisms of the formation of WLMs and the decrease in viscosity with glucose addition have not been determined. In this study, we elucidated the mechanisms using 3-fluorophenylboronic acid (3FPBA) based on 11B NMR and 19F NMR analyses. The system in 60 mM CTAB/60 mM 3FPBA at pH 7.4 demonstrated high viscoelasticity, and the formation of WLMs in the system was confirmed by rheological characteristics. The 11B NMR spectrum at pH 7.4 revealed that 3FPBA existed in a neutral form with sp2-hybridized boron; however, the 11B signal disappeared in the presence of CTAB. In contrast, 19F NMR studies indicated that the quaternary ammonium ion of CTAB interacts with the phenyl group of 3FPBA in the sp2 form via cation-π interactions. PBA derivatives react with various polyols; thus, we investigated the change in the viscous system after the addition of sugar and sugar alcohols. The viscosity of the WLMs decreased with increased polyol concentration, especially those of fructose and mannitol, in which the decrease was apparent at 40-160 mM polyols. The 19F NMR spectra revealed that polyol addition induced decrease in the sp2 form of 3FPBA and increase in the sp3 form of 3FPBA. Based on the results, we propose the following mechanism of the polyol response: (1) The WLMs are stabilized by CTAB and 3FPBA in the sp2 form using cation-π interactions as the driving force. (2) When polyol is added to the system, the sp2 form of 3FPBA decreases and its sp3 form increases. (3) This change means that the structural component of WLMs decreases, which induces the disruption of WLMs, and the viscosity decreases. The formation and deformation mechanisms of the WLMs determined in this study are notable because 3FPBA interacts as a neutral compound, whereas CTAB often interacts with anionic aromatic compounds to form WLMs. Without 19F NMR measurements, these mechanisms would not have been discovered.

Recoverable Palladium-Catalyzed Carbon-Carbon Bond Forming Reactions under Thermomorphic Mode: Stille and Suzuki-Miyaura Reactions.

The reaction of [PdCl2(CH3CN)2] and bis-4,4′-(RfCH2OCH2)-2,2′-bpy (1a–d), where Rf = n-C11F23 (a), n-C10F21 (b), n-C9F19 (c) and n-C8F17 (d), respectively, in the presence of dichloromethane (CH2Cl2) resulted in the synthesis of Pd complex, [PdCl2[4,4′-bis-(RfCH2OCH2)-2,2′-bpy] (2a–d). The Pd-catalyzed Stille arylations of vinyl tributyltin with aryl halides were selected to demonstrate the feasibility of recycling usage with 2a as the catalyst using NMP (N-methyl-2-pyrrolidone) as the solvent at 120–150 °C. Additionally, recycling and electronic effect studies of 2a–c were also carried out for Suzuki-Miyaura reaction of phenylboronic acid derivatives, 4-X-C6H4-B(OH)2, (X = H or Ph) with aryl halide, 4-Y-C6H4-Z, (Y = CN, H or OCH3; Z = I or Br) in dimethylformamide (DMF) at 135–150 °C. At the end of each cycle, the product mixtures were cooled to lower temperature (e.g., −10 °C), and then catalysts were recovered by decantation with Pd leaching less than 1%. The products were quantified by gas chromatography/mass spectrometry (GC/MS) analysis or by the isolated yield. The complex 2a-catalyzed Stille reaction of aryl iodides with vinyl tributyltin have good recycling results for a total of 8 times, with a high yield within short period of time (1–3 h). Similarly, 2a–c-catalyzed Suzuki-Miyaura reactions also have good recycling results. The electronic effect studies from substituents in both Stille and Suzuki-Miyaura coupling reactions showed that electron withdrawing groups speed up the reaction rate. To our knowledge, this is the first example of recoverable fluorous long-chained Pd-catalyzed Stille reactions under the thermomorphic mode.

Synthesis of (Trifluoromethyldiazirinyl)phenylboronic Acid Derivatives for Photoaffinity Labeling

Synthesis of (Trifluoromethyldiazirinyl)phenylboronic Acid Derivatives for Photoaffinity Labeling

Efficient recovery of bio-based 1,2,4-butanetriol by using boronic acid anionic reactive extraction

Effective isolation of 1,2,4-butanetriol (BT) from the fermentation broth with low BT concentration was achieved based on anionic reactive extraction with a combined extractant consisted of boronic acid carrier and trioctylmetylammonium Aliquat® 336 (A336) dissolved in the organic phase. The influence of various diluents, pH values, the ratio of phenylboronic acid derivatives (PBAD) to BT (αPBAD/BT), and A336 to BT (βA336/BT) on extraction property was investigated in detail. For model BT solutions, satisfactory extraction efficiency of 92% was obtained under the conditions of αPBAD/BT = 1.5, βA336/BT = 2, with dichloromethane as a diluent. Aqueous hydrochloric acid solutions were employed to strip BT from the organic phase. For actual fermentation broth, the extraction and stripping efficiency under the optimum conditions were 74% and 69%, respectively. Besides, compared with the original fermentation broth, 1,2,4-butanetriol has been concentrated by 4.6 times with the reactive extraction coupled hydrolysis.

Novel phenylboronic acid derivatives containing phosphorous and nitrogen as lubricant additives: Synthesis, characterization, and tribological behaviors

Three phenylboronic acid derivatives containing phosphorous and nitrogen with chlorine (BNP1), methyl (BNP2), and nitro (BNP3) were successfully prepared and applied to evaluate the tribological behaviors as additives in liquid paraffin. Three derivatives exhibited high thermal stability. The tribological tests indicated that three derivatives lead to a substantial improvement in anti-friction and anti-wear properties of liquid paraffin. In comparison to BNP1 and BNP3, BNP2 performs best on friction-reducing and wear resistance performances. This is caused by the strong electron-donating ability of the methyl group in BNP2. The analysis of worn surfaces demonstrated that three derivatives could form a protective tribofilm containing boron, nitrogen, and phosphorus elements on the rubbing surfaces. Thus, three phenylboronic acid derivatives could be potential lubricant additives in industrial applications.

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.

Recent Developments in the Immobilization of Palladium Complexes on Renewable Polysaccharides for Suzuki–Miyaura Cross-Coupling of Halobenzenes and Phenylboronic Acids

Polysaccharides derived from natural sources exhibit unique structures and functional groups, which have recently garnered them increased attention for their potential applicability as supports for metal catalysts. Renewable polysaccharide matrices were employed as supports for palladium complexes, with or without previous modification of the support, and were used in Suzuki cross-coupling of halobenzenes and phenylboronic acid derivatives. In this review, recent developments in the immobilization of palladium-based complexes are reported, including descriptions of the preparation procedures and catalytic activity of each system. In addition, the effects of the nature of the polymeric support and of the reaction conditions on catalytic performance are discussed.

Selective Sugar Recognition by Anthracene-Type Boronic Acid Fluorophore/Cyclodextrin Supramolecular Complex Under Physiological pH Condition.

We synthesized novel PET (photoinduced electron transfer)-type fluorescence glucose probe 1 [(4-(anthracen-2-yl-carbamoyl)-3-fluorophenyl)boronic acid], which has a phenylboronic acid (PBA) moiety as the recognition site and anthracene as the fluorescent part. Although the PBA derivatives dissociate and bind with sugar in the basic condition, our new fluorescent probe can recognize sugars in the physiological pH by introducing an electron-withdrawing fluorine group into the PBA moiety. As a result, the pKa value of this fluorescent probe was lowered and the probe was able to recognize sugars at the physiological pH of 7.4. The sensor was found to produce two types of fluorescent signals, monomer fluorescence and dimer fluorescence, by forming a supramolecular 2:1 complex of 1 with glucose inside a γ-cyclodextrin (γ-CyD) cavity. Selective ratiometric sensing of glucose by the 1/γ-CyD complex was achieved in water at physiological pH.

Copper quinolate: A simple and efficient catalytic complex for coupling reactions

We describe an effective and novel method to prepare N‐aryl imidazoles via the copper quinolate‐catalyzed N‐arylation of aryl halides and imidazoles. A wide range of products were obtained in moderate to excellent yields under the optimal reaction conditions. Applying standard conditions, the model reaction could be performed on a gram scale. This method also presents a new avenue to the “click” reaction of terminal alkynes, benzyl bromide, and sodium azide and to the construction of C–C bonds by homocoupling of phenylboronic acid or phenylacetylene derivatives with the aid of copper quinolate.

Synthesis, spectroscopic characterization and theoretical studies of (4-boronobenzoyl)serine

(4-boronobenzoyl)serine (4BBS) was synthesized and investigated theoretically and experimentally by spectroscopic methods such as FT-IR, Raman and NMR. The molecular structure, spectroscopic parameters and geometric parameters were determined by computational methods. All theoretical calculations were carried out using B3LYP method and 6-311++G(d,p) basis set. Total energy distribution analysis of normal modes was performed to identify characteristic frequencies. To investigate structure of title molecule using NMR, 1H, 13C, 13C APT, 1H-17O and 1H-15N HMQC, 1H-13C HMBC, 1H-13C HETCOR, 1H-1H NOESY and 1H-1H COSY NMR experiment were performed. These results should be useful for the experts in their studies based on functionalized phenylboronic acid derivatives.

A Versatile Strategy for Surface Functionalization of Hydrophobic Nanoparticle by Boronic Acid Modified Polymerizable Diacetylene Derivatives.

The flourishing advancements in nanotechnology significantly boost their application in biomedical fields. Whereas, inorganic nanomaterials are normally prepared and capped with hydrophobic ligands, which require essential surface modification to increase their biocompatibility and endow extra functions. Phenylboronic acid derivatives have long been known for its capacity for selective recognition of saccharides. Herein, we demonstrated a versatile surface modification strategy to directly convert hydrophobic inorganic nanocrystals into water-dispersible and targeting nanocomposites by employing boronic acid modified photo-polymerizable 10,12-pentacosadiynoicacid and further explore its potentials in selective cancer cell imaging.

Cell Adhesive Character of Phenylboronic Acid-Modified Insulin and Its Potential as Long-Acting Insulin

Phenylboronic acid (PBA) derivatives have attracted substantial attention owing to their unique character of forming dynamic covalent bonds with polyol compounds. Recent studies have shown interactions between PBA and sugar chains on the cell surface; they have interesting applications for sensors and drug delivery systems. In this study, we prepared phenylboronic acid-modified insulin (PBA-Ins) to evaluate its glucose-lowering activity and cell adhesiveness. In the case of intravenous injection, PBA-Ins showed longer glucose-lowering activity than native insulin. We hypothesized that this prolonged effect was the result of the interaction between the PBA moiety and sugar chains on the cell surface. Red blood cells (RBCs) were used as a cell model, and we confirmed PBA-Ins’s affinity for RBCs, which induced RBC agglutination. Interestingly, using an alternative PBA-Ins administration route markedly changed its glucose-lowering activity. Unlike the intravenous injection of PBA-Ins, the subcutaneous injection showed a small effect on glucose level, which indicated that a small amount of PBA-Ins was absorbed into the bloodstream. This suggested the importance of investigating the interaction between the PBA moiety and many types of cells, such as adipocytes, in subcutaneous tissues.

Controlled synthesis of three dimensional mesoporous C3N4 with ordered porous structure for room temperature Suzuki coupling reaction

We report on the synthesis of mesoporous graphitic C3N4 (MGCN-6) with 3D porous structure and Ia3d symmetry and controllable surface properties through a simple polymerization of an environmentally benign and non-toxic guanidine hydrochloride as a C and N precursor using KIT-6 with variable pore sizes as templates for Suzuki coupling reaction. The pore diameters (3.1–4.2 nm), specific surface areas (207–303 m2 g−1), and the specific pore volumes (0.58–0.71 cm3 g−1) of the MGCN-6 materials are finely controlled by varying the pore size of the templates used. The nano cavities of MGCN-6 with the highest specific surface area and a free amine groups are effectively utilized to chelate with Pd(OAC)2 and applied the prepared catalysts for Suzuki coupling reaction between aryl halides with phenylboronic acid derivatives under very mild and sustainable reaction conditions. The Pd(OAC)2/MGCN-6 is found to be very active and stable and exhibits an excellent reactivity and selectivity for all of substrates regardless of aryl halides with electron-withdrawing and electron donating groups at room temperature. The activity of the Pd(OAC)2/MGCN-6 is much higher than that of non-porous bulk graphitic carbon nitride and 2D mesoporous carbon nitride.

Anti-proliferative Activities towards Human Brain Glioma U251 Cells and Human Carcinoma Cells (KB3-1) of Some Twin-Drug Type Bivalent C2-Symmetrical Phenylboronic Acid Derivatives.

Derivatives of C2-symmetrical bivalent phenylboronic acid exhibit several remarkable biological activities such as anti-herpes simplex virus (HSV)-1 and cytotoxic activities against Vero cells and they can reverse the effect of anticancer drugs. Novel symmetrical bivalent molecules were synthesized and their biological activities were evaluated in vitro using a human brain glioma cell line (U251) and a human carcinoma cell line (KB3-1). Among the tested compounds (1a-i), bivalent C2-symmetrical phenylboronic acid derivative 1g showed the highest anti-proliferative activity towards both U251 and KB3-1 cells. The values of 50% anti-proliferative activity (IC50) of this compound against the two cell lines (U251 and KB3-1) were 19.0 and 3.78 µM, respectively. The anti-proliferative activity of compound 1g towards KB3-1 cells was higher than that of cisplatin. The bivalent C2-symmetrical compound 1g had a linear methylene linker in the molecule.