Copper-mediated synthesis of N,N'-diarylhydrazines from boronic acids

N,N＇-Diarylhydrazines have been prepared via the reaction of N-Boc-aryl hydrazines with boronic acids mediated by copper acetate. This mild reaction condition tolerates the presence of a variety of functional groups.

A High Sensitive LC-MS/MS Method for the Simultaneous Determination of Potential Genotoxic Impurities Carboxy Phenyl Boronic Acid and Methyl Phenyl Boronic Acid in Lumacaftor

A simple, rapid, and highly sensitive LC-MS/MS method has been developed for the simultaneous and trace level quantification of underivatized boronic acids in lumacaftor active pharmaceutical ingredient. Chromatographic separation of boronic acids and lumacaftor achieved using Agilent Poroshell HPH C18 150 × 4.6 mm 2.7 μ column with 0.1% ammonia in water as mobile phase A and 100% acetonitrile as mobile phase B at a flow rate of 0.25 ml/min. Gradient elution was used with a total method run time of 14 minutes. Boronic acids were successfully ionized and quantified without derivatization using electrospray ionization in negative mode using tandem quadrupole mass spectrometry in multiple reactions monitoring mode. Method validation was performed as per ICH guidelines with good linearity over the concentration range of 0.05 ppm to 5 ppm of Lumacaftor test concentration for both the boronic acids with a correlation coefficient of >0.99. Recoveries were found good at different concentration levels and within the range of 80% - 120%. The developed method can be successfully used for the routine quantification of boronic acids at a concentration level of 20 ng/ml (1 ppm with respect to 20 mg/ml lumacaftor).

Room temperature spontaneous surface condensation of boronic acids observed by scanning tunneling microscopy

Herein,we discovered that the surface-confined condensation of boronic acid can happen spontaneously at room temperature,by comparing the kinetics of condensation of boronic acids with and without the negative sample bias,we found that the negative sample bias indeed accelerates the self-condensation reaction of boronic acid.Combining with in-situ STM images and ultraviolet photoemission spectrum(UPS)analysis,a reversible adsorption mechanism model was proposed and reasonably explains the reversible electric-field-induced phase transformation.

A photoactivatable and phenylboronic acid-functionalized nanoassembly for combating multidrug-resistant gram-negative bacteria and their biofilms

Background:Multidrug-resistant(MDR)gram-negative bacteria-related infectious diseases have caused an increase in the public health burden and mortality.Moreover,the formation of biofilms makes these bacteria difficult to control.Therefore,developing novel interventions to combat MDR gram-negative bacteria and their biofilms-related infections are urgently needed.The purpose of this study was to develop a multifunctional nanoassembly(IRNB)based on IR-780 and N,N-di-sec-butyl-N,N-dinitroso-1,4-phenylenediamine(BNN6)for synergistic effect on the infected wounds and subcutaneous abscesses caused by gram-negative bacteria.Methods:The characterization and bacteria-targeting ability of IRNB were investigated.The bac-tericidal efficacy of IRNB against gram-negative bacteria and their biofilms was demonstrated by crystal violet staining assay,plate counting method and live/dead staining in vitro.The antibacterial efficiency of IRNB was examined on a subcutaneous abscess and cutaneous infected wound model in vivo.A cell counting kit-8 assay,Calcein/PI cytotoxicity assay,hemolysis assay and intravenous injection assay were performed to detect the biocompatibility of IRNB in vitro and in vivo.Results:Herein,we successfully developed a multifunctional nanoassembly IRNB based on IR-780 and BNN6 for synergistic photothermal therapy(PTT),photodynamic therapy(PDT)and nitric oxide(NO)effect triggered by an 808 nm laser.This nanoassembly could accumulate specifically at the infected sites of MDR gram-negative bacteria and their biofilms via the covalent coupling effect.Upon irradiation with an 808 nm laser,IRNB was activated and produced both reactive oxygen species(ROS)and hyperthermia.The local hyperthermia could induce NO generation,which further reacted with ROS to generate ONOO−,leading to the enhancement of bactericidal efficacy.Furthermore,NO and ONOO−could disrupt the cell membrane,which converts bacteria to an extremely susceptible state and further enhances the photothermal effect.In this study,IRNB showed a superior photothermal-photodynamic-chemo(NO)synergistic therapeutic effect on the infected wounds and subcutaneous abscesses caused by gram-negative bacteria.This resulted in effective control of associated infections,relief of inflammation,promotion of re-epithelization and collagen deposition,and regulation of angiogenesis during wound healing.Moreover,IRNB exhibited excellent biocompatibility,both in vitro and in vivo.Conclusions:The present research suggests that IRNB can be considered a promising alternative for treating infections caused by MDR gram-negative bacteria and their biofilms.

Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1NNRTIs: Design, synthesis and biological evaluation

Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.

Boronic acid-rich dendrimer for efficient intracellular peptide delivery

Interests in intracellular peptide delivery have continued to grow,significantly fueled by the importance of peptides and their mimetics in modern cell biology and pharmaceutical industry.However,efficient intracellular delivery of membrane-impermeable peptides of different polarities remains a challenging task.In this study,we develop a general and robust strategy for intracellular peptide delivery by using a boronic acid-rich dendrimer.The designed material is capable of transporting peptides with different polarities and charge properties into the cytosol of various cell lines without inducing additional cytotoxicity.The transduction efficacy and proteolytic stability of cargo peptides delivered by the boronic acid-rich dendrimer are much superior to peptides conjugated with cell penetrant peptides such as octaarginine.In addition,the bioactivities of pro-apoptotic peptides are maintained after intracellular delivery.This study provides a versatile and robust platform for the intracellular delivery of membrane-impermeable peptides.

Highly Efficient Synthesis of Arylpyrrole Derivatives via Rh（lll）-Catalyzed Direct C--H Arylation with Aryl Boronic Acids

An efficient and facile method for synthesis of 2-arylpyrroles through Rh（III）-catalyzed direct C--H arylation with pyrrole derivatives and aryl boronic acids has been developed. This reaction could proceed under mild reaction conditions and afford a series of 2-arylated products in good to excellent yields. The gram-scale experiment has been conducted to demonstrate the synthetic potential of this methodology.

Oriented Antibody Immobilization and Immunoassay Based on Boronic Acid-containing Polymer Brush

High sensitive immunoassay platforms have gained intense attention due to their vital roles in early-stage disease diagnosis and therapeutic information feedback. Although random covalent-binding of antibody has been widely adopted in immunoassays due to its simplicity and effectiveness, it readily loses its activity and fails to exhibit high antigen-binding capacity. In this work, copolymer of zwitterionic sulfobetaine methacrylate（SBMA） and glycidyl methacrylate（GMA） brushes were immobilized onto inert polypropylene（PP） via surface-initiated atom transfer radical polymerization（ATRP） based on biomimetic dopamine pretreatment. Subsequently, boronic acid（BA） groups were covalently bonded via active GMA units, followed by the introduction of oriented immobilization of antibody. Owing to the oriented immobilization of antibody facilitated by BA groups in polymer brush, the bioactivity of antibody is well preserved, which endows the surface with significantly enhanced antigen-binding capacity. Moreover, the existence of SBMA segments in polymer brushes renders the surface high resistance to nonspecific protein adsorption, significantly alleviating the signal interference of antigen recognition. This strategy could find potential applications in developing high sensitive immunoassay platforms based on the different substrates.

One-pot synthesis of N-aryl propargylamine from aromatic boronic acid,aqueous ammonia,and propargyl bromide under microwave-assisted conditions

A facile,one-pot synthesis of N-aryl propargylamine from aromatic boronic acid,aqueous ammonia,and propargyl bromide has been achieved under microwave-assisted conditions.The reactions can be smoothly completed within a total 10 min through a two-step procedure,including copper-catalyzed coupling of aromatic boronic acids with aqueous ammonia and following propargylation by propargyl bromide.

Boronic acid-containing carbon dots array for sensitive identification of glycoproteins and cancer cells

Discrimination of glycoproteins and cell types is a significant but difficult issue.Herein,we presented a novel fluorescence sensor array for the detection and identification of glycoproteins and cancer cells based on the specific affinity between boronic acid-containing carbon dots(BA-CDs)and cis-diol residues of polysaccharides.The differential binding affinity of three BA-CDs to various glycoproteins resulted in a different fluorescence turn-on signal pattern caused by aggregation-enhanced emission(AEE),along with negligible response from other proteins.Therefore,BA-CDs encompassing sensing elements and signal indicator into one can enable a fast and accurate discrimination of glycoproteins with simple and easy operation.Seven glycoproteins could be well discriminated at a very low concentration of 10 nmol/L.The discriminating capability of glycoproteins is not sacrificed in both human urine and serum.Notably,different glycoprotein compositions of cancer cells provide more recognizable features for identification of cancer cells,comparing to the total protein.Five cell types could be identified in 15 min at a low concentration of 1000 cells/mL.This method is fast,accurate,and easy operation,and has a potential application in cancer diagnosis.

Rh（Ⅰ）-Catalyzed Arylation of α-Diazo Phosphonates with Aryl Boronic Acids： Synthesis of Diarylmethylphosphonates

An efficient synthetic method for diarylmethylphosphonates is presented.A series of phosphonate derivatives with diverse functional groups can be accessed via a rhodium catalyzed cross-coupling reaction between a-diazo phosphonates and aryl boronic acids.Migratory insertion of rhodium carbene intermediates is postulated to be the critical step in this transformation.

Efficient N-heterocyclic carbene nickel pincer complexes catalyzed cross coupling of benzylic ammonium salts with boronic acids

Pyridine-bridged bis-benzimidazolylidene nickel complexes exhibited very high catalytic activity toward cross coupling of inactive（hetero）aryl benzylic ammonium salts with（hetero）aryl and alkenyl boronic acids under mild reaction conditions.Even at 2 mol% catalyst loading,a wide range of substrates for both coupling partners with different steric and electronic properties were well tolerated.

Analysis of the linkage positions and isomers of monosaccharide units in oligosaccharides by negative secondary ion mass spectrometry in combination with the stereoselective reaction with substituted boronic acid

The negative secondary ion mass spectrometry,in combination with the stereoselective derivatizations with substituted boronic acid RB(OH)_2,was used in the analysis of fourteen oligosac- charides.The mass spectra of the derivatives provide information on their linkage Positions and iso- merism of the individual monoscaccharide units.The results indicated that among the derivatives of the oligosaccharides analyzed,those with 1—4 and 1—6 linkages all presented the ion peaks at m/z 287,sometimes one more peak at m/z 449.Furthermore,a relationship was found between the linkage positions and the intensity orders of the derivative ions.Finally,the derivatives of the disaccharides with a galactose presented an intense ion peak at m/z 347,and those of oligosaccharides with 1—6 linkage to a galactose at terminal presented the ion at m/z 317.In the case of oligosaccharides with a fructose residue,characteristic ion of m/z 155 was produced.The conditions of stereoselective derivatizations and mass spectrometry were studied,in order to obtain a better reproducibility of the mass spectra.

Synthesis and Single Crystal X-ray Studies of 3-(3,5-Bis(trifluoromethyl)phenyl) Quinoline and 3-(4-Fluoro-3-methylphenyl) Quinoline

The title compounds 3-（3,5-bis（trifluoromethyl）phenyl）quinoline （1） and 3-（4- fluoro-3-methylphenyl）quinoline （2） were synthesized through Suzuki-Miyaura Cross coupling reaction of 3-bromoquinoloine with aryl boronic acids. The title compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR, El-MS, elemental analysis and IR. The crystals of 3-（3,5-bis（trifluoromethyl）phenyl）quinoline （C17H9F6N, Mr = 341.25） belongs to the monoclinic system, space group P21n, a = 12.3072（13）, b = 4.9378（6）, c = 24.493（2） A, V= 1473.1（3） A3, Z = 4, Dc = 1.539 Mg m-3, 2 - 0.71073A, μ = 0.144 mm^-1, F（000） = 688, the final R = 0.0715 and wR = 0.1873 for 1875 obserwed reflections with I 〉 2σ（I） and the crystal of 3-（4-fluoro-3- methylphenyl）quinoline （C16H12FN, Mr= 237.27） belongs to the orthorhombic system, space group Pca21, a = 23.794（2）, b = 3.9094（3）, c = 25.669（2） A, V = 2387.7（4） A3, Z = 8, D, = 1.320 Mg m-3, 2 = 0.71073 A, μ = 0.088 mm-1, F（000） = 992, the final R = 0.0534 and wR = 0.1188 for 2270 observed reflections with I 〉 2σ（I）.

Cu2O-Mediated Room Temperature Cyanation of Aryl Boronic Acids/Esters and TMSCN

A method for the efficient and reliable synthesis of aryl nitriles via the Cu20-catalyed cross-coupling of aryl boronic acids or esters and TMSCN is presented. A broad range of substrates decorated by electron-rich and defi- cient, sterically very congested, and labile functionalities were tolerated. Moreover, the reaction can proceed under mild conditions at room temperature. These advantages paired with the use of cheap, readily available, and halo- gen-free Cu20 as catalysts make the protocol an appealing option for aryl cyanations.

A Long-Wavelength Fluorescent Probe for Saccharides Based on Boronic-Acid Receptor

A single boronic acid-based fluorescent probe （compound CSP） for saccharides was designed and synthesized. The probe, with an a,fl-unsaturated ketone conjugated into the coumarin fluorophore, was synthesized by 4 steps from the commercial material 4-diethylamino salicylaldehyde. The electron push-pull effect is enhanced with the N,N-diethyl amino as the electron donor and the carbonyl as the electron acceptor. Both the absorption （463 nm） and emission （616 nm） maxima of CSP are in the visible wavelength region with a Stokes shift of about 150 nm, which ensures CSP a potential probe for biological application. Under near physiological conditions, significant fluores- cence enhancement of CSP was observed upon the addition of some saccharides, namely, D-sorbitol, D-fructose, D-glucose, D-mannose and D-galactose. The probe showed relatively high sensitivity towards D-fructose and D-sorbitol, and their detection limits were 0.05 mmol/L and 0.1 mmol/L, respectively.

A Novel Nucleobase Modification Strategy for Controlling RNA-Guided Nucleic Acid Cleavage

Clustered regularly interspaced short palindromic repeat(CRISPR)technologies have opened new scientific avenues widely used in biomedical research.But simple and efficient strategies to reversibly control CRISPR are lacking.In contrast to previous methods of attaching molecules to the ribose of guide RNAs(gRNAs),we focused on molecules that can directly react with nucleobases.Here,we developed a new strategy to switch off the CRISPR system by efficiently installing 4-(bromomethyl)phenylboronic acid onto nucleobases in gRNAs.CRISPR can then be activated by hydrogen peroxide(H_(2)O_(2)).Collectively,this work demonstrates boronic acid reversibly modulating CRISPR systems through a H_(2)O_(2)-responsive manner.

Tribological behavior of hot-pressed boron carbide with oxidation

The oxidation behavior at 973 1 273 K and the effect of oxidation on the room temperature tribological properties of hot pressed boron carbide ceramic were investigated. Oxidized samples were studied by X ray diffractometer and scanning electron microscopy. It is demonstrated that the oxidation results in the formation of a thin transparent B 2O 3 film, and the oxide film is severely cracked during cooling due to the thermal expansion mismatch between the oxide film and B 4C substrate. B 2O 3 reacts with moisture in air to form boric acid, which is a kind of solid lubricant. The sliding friction factors of oxidized B 4C pair are about 0.05 0.08, compared to 0.25 0.35 of the as received B 4C pair. When the oxidation temperature is up to 1 273 K, severe unstability and increase of friction factor are observed. Visual inspection of the wear track reveals that the lubricant film is broken and some debris particles occur on and around the rubbing surfaces, because the friction interface is rough by the severe etching of grain boundaries.

Quantitative detection of citrate for early stage diagnosing of prostate cancer:Discriminating normal to cancer in prostate tissues

Prostate cancer(PC)biomarker-citrate detection is clinically important to diagnose PC in early stages.Methylquinolinium iodide(Q)conjugated indole-phenylboronic acid(IB)was designed as a red-emissive QIB probe for the detection of citrate through Lewis acid-base reaction and intramolecular charge transfer(ICT)sensing mechanisms.Boronic acid acts as Lewis acid as well as citrate(Lewis base)recognition unit.The probe reacted with citrate,showing enhanced red emissions.Since the probe has excellent water solubility and great biocompatibility,practical application in biological systems is possible.Citrate was monitored precisely in the mitochondria organelle(in vitro)of living cells with a positive charge on QIB.Also,endogenous(in situ)citrate was detected quantitatively to discriminate non-cancerous and PC mice,observed strong and lower(negligible)emission intensity on non-cancerous and cancerous prostate tissues,respectively.Because,the concentration of citrate is higher in healthy prostate compared with PC prostate.Furthermore,the analysis of sliced prostate tissues can give PC-related information for clinical diagnosis to prevent and treat PC in the initial stages.Therefore,we believe that the present probe is a promising biochemical reagent in diagnosing PC.

Synthesis of unnatural N-glycosyl α-amino acids via Petasis reaction

A convenient and efficient protocol for the synthesis of unnatural N-glycosyl cz-amino acids was developed. Condensation of 1,3,4,6-tetra-O-actyl-/%D-glucosamine hydrochloride, alkenyl boronic acid, and glyoxylic acid was achieved in CH2C12 to give the derivatives of 2-（N-glycosyl）aminobut-3-enoic acid which may find applications in glycobiology research and medicinal chemistry.