Phenylboronic acid functionalized polyacrylonitrile fiber for efficient and green synthesis of bis(indolyl)methane derivatives

The use of fiber as a catalyst carrier to construct heterogeneous catalysts with good catalytic activity and recycling performance has received wide attention.In this study,three phenylboronic acid functionalized polyacrylonitrile fiber(PANF)catalysts were synthesized by amination and quaternization.Fourier transform infrared spectroscopy,X-ray diffractometry,scanning electron microscopy,and X-ray photoelectron spectroscopy were used to verify the successful grafting of phenylboronic acid and the structural integrity of the fiber catalyst after recycling.The activity of the catalysts was explored with the Friedel–Crafts alkylation between indole and aromatic aldehydes.The results indicate that the synthesized catalyst(PANp-BAF)in which the phenylboronic acid functional group was linked at the para position,exhibited the highest catalytic activity for the Friedel–Crafts alkylation.The substrate scope experiments confirmed that the catalyst has outstanding catalytic activity for most aromatic aldehydes,especially for those containing moderate electron donating groups.Moreover,the catalyst can be reused eight times in water without significant decrease in its catalytic activity.Further,the scale-up experiment confirmed that the fiber catalyst has a certain potential for industrial application.

Preparation and properties of poly(ethylene glycol)-bpoly( 3-acrylamidophenylboronic acid) glucose responsive particles and their hyaluronic acid-based microneedle patches

To overcome the pain and risk of hypoglycemia in insulin administration,glucose-responsive microneedles have been developed by researchers,which could release insulin according to the blood glucose level.We designed a kind of particles by a reversible addition-fragmentation chain transfer(RAFT)method containing a phenylboronic acid group as the sensor of glucose and carrier of insulin.poly(ethylene glycol)(PEG)-2-(dodecylthio(thiocarbonyl)thio)-2-methylpropionic acid(DDMAT)was synthesized as a macromolecular RAFT agent,which was then reacted with 3-acrylamidophenylboronic acid(AAPBA)to synthesize the block copolymer PEG-b-PAAPBA.Glucose-responsive particles loaded with insulin were prepared by self-assembly based on hydrophilic-hydrophobic interactions.Microneedle patches loaded with glucose-responsive particles were prepared using hyaluronic acid as the substrate.The insulin release behavior of the particles in glucose solutions of 0,100,and 400 mg/dL showed significant glucose responsiveness and good biosafety.The results of blood glucose control experiments in rats indicate that a single microneedle patch can effectively maintain normal blood glucose for over 7 h.

Structural effect of fluorophore on phenylboronic acid fluorophore/cyclodextrin complex for selective glucose recognition

Based on the design of the fluorescent site of a fluorescent probe,we have created a unique system that changes its twisting response to sugar.Two probes were synthesized,in which phenylboronic acid and two kinds of aromatic fluorescent site(pyrene or anthracene)were conjugated by an amide bond.In the fluorescence measurement of pyrene-type probe 1,dimer fluorescence was observed at high pH.In induced circular dichroism(ICD)experiments,a response was observed only in the presence of glucose and γ-cyclodextrin,and no response was seen with fructose.On the other hand,in the fluorescence measurement of anthracene-type probe 2,dimer fluorescence was observed in the presence of both glucose and galactose,and the fluorescence was different from the case of fructose.When the ICD spectra of these inclusion complexes were measured,an inversion of the Cotton effect,which indicates a change in the twisted structure,was observed in galactose and glucose.These differences in response to monosaccharides may originate in the interaction between the fluorescent site and the cyclodextrin cavity.

Stereochemical effects in mass spectrometry——Ⅺ.Negative ion fast atom bombardment mass spectrometry of saccharides and glycosides using phenylboronic acid as reagent

The negative ion fast atom bombardment (NIFAB) mass spectra of mono-,di-saccharides and glycosides using phenylboronic acid (PBA) as reagent have been studied.In the ion source,PBA reacts stereospecifically with the molecules containing cis-vicinal glycols to form characteristic ions, from which the stereo-isomers of saccharides can be definitely distinguished.Disaccharides and glyco- sides with β-glycosidic linkage seem to be unfavorabale to react with PBA,therefore,by comparison of the abundances of the characteristic ions,the configuration of the glycosidic linkage in these compounds may be inferred.

Detection of Lectins by Saccharide-gold Nanoparticle Conjugates

A general functionalization strategy was reported,which enables one to conjugate saccharide（SA） on gold nanoparticle（GNP） surface without affecting SA properties.First,disulfide phenylboronic acid（Bor） functionalized GNPs（Bor@GNPs） were synthesized by the reaction of citrate stabilized GNPs of 13 nm in diameter with the mixture of Bor and pentapeptide（Cys-Ala-Leu-Asn-Asn,CALNN）.Subsequently,the SA-GNP conjugates（SA@GNPs） were prepared by coupling SA to the GNP surface via the reaction of phenylboronic acid（PBA） with the cis-diol configuration in SA.The interactions of three SA@GNPs with three lectins have been analyzed by UV-visible spectroscopic and transmission electronic microscopic（TEM） techniques,respectively.The experimental results demonstrate that SA@GNPs can efficiently bind to lectins and show a great promise as optical probes for monitoring specific affinities of lectins for SA,and detecting lectins with high sensitivity.

Carbonylative Coupling of 4,4’-Diiodobiphenyl Catalyzed by Pd(NHC) Complex

To develop a luminescent material with high color purity, luminous efficiency, and stability, we synthesized diketone by carbonylative Suzuki coupling in the presence of Pd(NHC) complex as the catalyst. Carbonylative coupling of 4,4’-diiodobiphenyl and phenylboronic acid was investigated to study in detail the catalytic ability of the Pd(NHC) complex. Reactions were carried out using both CO and metal carbonyls. Bis-(1,3-dihydro-1,3-dimethyl-2H-imidazol- 2-ylidene) diiodo palladium was used as the catalytic complex. Reaction products biphenyl-4,4’-diylbis (phenyl- methanone) 3 and (4’-iodobiphenyl-4-yl)(phenyl) methanone 4 were obtained as a result of CO insertion into the palladium(II)-aryl bond. However, when pyridine-4-yl boronic acid was used in place of phenylboronic acid as the starting reagent, synthetic reaction yielding 3 and 4 were found not to occur.

IL-2-loaded Polypeptide Nanoparticles for Enhanced Anti-cancer Immunotherapy

Interleukin 2 (IL-2) is widely used as an active immunotherapeutic agent in clinical metastatic cancers. However, its therapeutic concentrations do not last long due to its short half-life. Thus, only a transient proliferation of the anti-cancer CD8+ T cells can be achieved, resulting in poor efficacy. Therefore, the aim of this work was to create a system that promotes CD8+ T cell proliferation at the tumor site using IL-2 persistently present and activates an anti-cancer immune response. This goal was achieved by the design of the IL-2-loaded polypeptide nanoparticles (P-IL-2) where methoxy poly(ethylene glycol) block poly-[(N-2-hydroxyethyl)-aspartamide] phenylboronic acid was used to encapsulate IL-2 through boron-nitrogen coordination with poly(L-lysine). P-IL-2 significantly prolonged the circulation time of IL-2 and achieved a selective drug release at the tumor site in the presence of high levels of reactive oxygen species, thus activating an anti-cancer immune response and exerting a better anti-cancer effect. The half-life of P-IL-2 was 3.15-fold higher than that of IL-2, and the quantity of CD8+ T cells after using P-IL-2 was 1.89-fold higher than that after using IL-2. In addition, the combination of P-IL-2 and anti-CTLA-4 monoclonal antibody resulted in an enhanced immune activation. Hence, this work provides a new approach to improve the efficacy of IL-2 in anti-cancer immunotherapy.

A boronic acid conjugation integrates antitumor drugs into albumin-binding prodrugs-based nanoparticles with robust efficiency for cancer therapy

Despite great therapeutic effect of Abraxane®,complex preparation technology and unfavorable pharmacokinetics still restricted the clinical application of albumin-based paclitaxel(PTX)nanoparticles(NPs).Herein,we reported that an albumin-binding prodrug,phenylboronic acid-conjugated PTX(P-PTX),can form the uniform NPs with the diameters around 100 nm with the help of albumin via simple one-step nano-precipitation method.The albumin-based nanomedicines were stabilized by the integration of a single boronic acid with PTX due to the increased affinity based on multiple intermolecular interactions.We found that albumin-based P-PTX NPs exhibited superior colloidal stability over albumin-based PTX NPs through one-step nanoprecipitation approach,achieving longer in vivo circulation time and higher concentration in tumor than those of the marketed Abraxane®.Furthermore,the albumin-based P-PTX NPs with great stability and enhanced intratumoral enrichment,increased the maximum tolerated dose of PTX,remarkably suppressed the growth of breast tumor and lung metastasis,prolonged survival of melanoma tumors-bearing mice.Such a convenient and effective system gains an insight into the impact of phenylboronic acid group on the albumin-based PTX NPs,provides potent strategy for the rational design of albumin-based antitumor nanomedicines.

Injectable dual glucose-responsive hydrogel-micelle composite for mimicking physiological basal and prandial insulin delivery

For type 1 and advanced type 2 diabetic patients, insulin replacement therapy with simulating on-demand prandial and basal insulin secretion is the best option for optimal glycemic control. However, there is no insulin delivery system yet could mimic both controlled basal insulin release and rapid prandial insulin release in response to real-time blood glucose changes. Here we reported an artificial insulin delivery system, mimicking physiological basal and prandial insulin secretion, to achieve real-time glycemic control and reduce risk of hypoglycemia. A phenylboronic acid(PBA)/galactosyl-based glucose-responsive insulin delivery system was prepared with insulin-loaded micelles embedded in hydrogel matrix. At the hyperglycemic state, both the hydrogel and micelles could swell and achieve rapid glucose-responsive release of insulin, mimicking prandial insulin secretion.When the glucose level returned to the normal state, only the micelles partially responded to glucose and still released insulin gradually. The hydrogel with increased crosslinking density could slow down the diffusion speed of insulin inside, resulting in controlled release of insulin and simulating physiological basal insulin secretion. This hydrogel-micelle composite insulin delivery system could quickly reduce the blood glucose level in a mouse model of type 1 diabetes, and maintain normal blood glucose level without hypoglycemia for about 24 h. This kind of glucose-responsive hydrogel-micelle composite may be a promising candidate for delivery of insulin in the treatment of diabetes.

Practical copper-catalyzed N-arylation of amines with 20% aqueous solution of n-Bu_4NOH

N-Arylation of a wide variety of amines with phenylboronic acid catalyzed by copper acetate under 20%aqueous solution of n-Bu_4NOH was accomplished in good to excellent yields（up to 92%） and substrate conversions（up to 96%）.

Responsive boron biomaterials and their biomedical applications

Due to the formation of dynamic boronate ester bonds between phenylboronic acid(PBA) and 1,2-and 1,3-diols, PBAcontaining biomaterials show increasing applications in biomedical areas, including responsive nanobiomaterials for targeting delivery of chemical drugs, protein drugs, gene drugs and imaging agents in vitro and in vivo for detection of various bioactive molecules such as sialic acid, saccharides, adenosine triphosphate(ATP) and dopamine. With the specific reaction between PBA and sialic acid, which is overexpressed in many kinds of cancer cells, PBA has been used as a targeting moiety for tumortargeting drug delivery. Additionally, PBA as an electron acceptor affords nanomaterials Lewis acid-base coordination with electron donor atoms such as nitrogen and oxygen, which can be exploited for developing drug delivery systems with high drug loading. Furthermore, PBA-containing materials can stoichiometric consume reactive oxygen species(ROS) and show a nucleus targeting ability. This current review outlined PBA-containing biomaterials with various responsive abilities including sialic acid-targeting, sugars-binding, ROS-response, ATP-response, dopamine-binding, and nuclear targeting. On this basis, their biomedical applications were summarized.

Mechanistic insights into the novel glucose-sensitive behavior of P(NIPAM-co-2-AAPBA)

A glucose-sensitive polymer,poly(N-isopropylacrylamide-co-2-acrylamidophenylboronic acid)(P(NIPAM-co-2-AAPBA)),was synthesized by reversible addition fragmentation chain transfer(RAFT)copolymerization.Addition of glucose results in reduced solubility and hence increased turbidity,rather than the normal increase in solubility(decreased turbidity)observed for other PBA-based glucose-sensitive polymers.The novel glucose-sensitive behavior is explained by a new mechanism,in which glucose acts as an additive and depresses the lower critical solution temperature(LCST)of the polymer,instead of increasing solubility by increasing the degree of ionization of the PBA groups.Experimental and theoretic analysis for the influence of glucose on the thermal behavior of P(NIPAM-co-2-AAPBA)reveals that glucose depresses the LCST of P(NIPAM-co-2-AAPBA)copolymers in a two-stage manner,a fast decrease at low glucose concentrations followed by a slow decrease at high glucose concentrations.For low glucose concentrations,the binding of glucose with PBA groups on the polymer chain increases the number of glucose molecules proximal to the polymer which influences the thermal behavior of the polymer,causing a rapid decrease in LCST.Importantly,the transition occurs at a glucose concentration equal to the reciprocal of the binding constant between PBA and glucose,thus providing a novel method to determine the binding constant.Other saccharides,including mannose,galactose and fructose,also depress the LCST of P(NIPAM-co-2-AAPBA)copolymer in the same way.

Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phe- nylboroinc Acid Based Low-molecular-weight Gelators

The physical environment plays a critical role in modulating stem cell differentiation into specific lineages. In this study, we designed and synthesized a series of low-molecular-weight gels （LMWGs） with different moduli based on phenylboronic acid derivatives. The moduli of the LMWGs were readily tuned by varying the alkyl chain without any chemical crosslinker. The cell responses to the gels were evaluated with mesenchymal stem cell （MSCs）, in respect of cell morphology, proliferation and differentiation. The prepared gels were non-toxic to MSCs, suggesting good biocompatibility. The hydrogel stiffness exerted a striking modulation effect on MSC fate decisions, where MSCs were inclined to differentiate into osteoblasts in stiff LMWGs and into chondrocytes in soft LMWGs. The pivotal elastic modulus of the LMWGs to drive MSC differentiation into osteoblastic lineage and chondrocytic lineage were approximately 20 kPa - 40 kPa and 1 kPa - 10 kPa, respectively. Overall, our results demonstrated that the modification ofhydrogel stiffness via tuning the alkyl chain was a simple but effective approach to regulate MSC differentiation into specific lineage, which might have important implications in the design of LMWGs for tissue engineering applications.

An ROS-Responsive Antioxidative Macromolecular Prodrug of Caffeate for Uveitis Treatment

Uveitis is a sophisticated syndrome showing a high relevance with reactive oxygen species(ROS).Herein,an ROS-responsive PEGylated polypeptide based macromolecular prodrug of herbaceous antioxidant ethyl caffeate(EC)is designed via phenylboronic esters with improved solubility for the alleviation of uveitis.The antioxidative 4-hydroxybenzyl alcohol(HBA)and EC can be released from the macromolecular EC prodrug under the stimulation of ROS,which can effectively protect cells against oxidative stress-induced injury in an ROS-depletion way.The antioxidative and protective effects of the macromolecular EC prodrug in vivo are further verified in a uveitis mouse model.Overall,this work not only provides a handy method to synthesize a phenylboronic ester-bearing EC prodrug which is highly sensitive to pathological ROS,but also depicts a promising future to apply macromolecular antioxidative prodrugs in the treatment of uveitis as well as other ROS-related diseases.