Pyridine Boronic Acid Research Articles

Corrigendum: Corrigendum to the Publication “A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids”

Corrigendum: Corrigendum to the Publication “A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids”

An alkaline phosphatase-induced immunosensor for SARS-CoV-2 N protein and cardiac troponin I based on the in situ fluorogenic self-assembly between N-heterocyclic boronic acids and alizarin red S

Alkaline phosphatase (ALP)-induced in situ fluorescent immunosensor is less investigated and reported. Herein, a high-performance ALP-labeled in situ fluorescent immunoassay platform was constructed. The developed platform was based on a fluorogenic self-assembly reaction between pyridineboronic acid (PyB(OH)2) and alizarin red S (ARS). We first used density functional theory (DFT) to theoretically calculate the changes of Gibbs free energy of the used chemicals before and after the combination and simulated the electrostatic potential on its′ surfaces. The free ARS and PyB(OH)2 exist alone, neither emits no fluorescence. However, the ARS/PyB(OH)2 complex emits strong fluorescence, which could be effectively quenched by PPi based on the stronger affinity between PPi and PyB(OH)2 than that of ARS and PyB(OH)2. PyB(OH)2 coordinated with ARS again in the presence of ALP due to the ALP-catalyzed hydrolysis of PPi, and correspondingly, the fluorescence was restored. We chose cTnI and SARS-CoV-2 N protein as the model antigen to construct ALP-induced immunosensor, which exhibited a wide dynamic range of 0–175 ng/mL for cTnI and SARS-CoV-2 N protein with a low limit of detection (LOD) of 0.03 ng/mL and 0.17 ng/mL, respectively. Moreover, the proposed immunosensor was used to evaluate cTnI and SARS-CoV-2 N protein level in serum with satisfactory results. Consequently, the method laid the foundation for developing novel fluorescence-based ALP-labeled ELISA technologies in the early diagnosis of diseases.

A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids.

Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using pyridine containing boronic acid building blocks to increase the water solubility. Following our initial publication in which we have introduced the methodology in combination with sequential Pd‐catalyzed cross‐coupling for teraryl assembly, we can now report a complete set of pyridine based boronic acid building blocks decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr, Val) to complement the core fragment set. For a representative set of teraryls we have studied the influence of the pyridine rings on the solubility of the assembled oligoarenes.

3-Pyridinylboronic Acid Ameliorates Rotenone-Induced Oxidative Stress Through Nrf2 Target Genes in Zebrafish Embryos.

Parkinson's disease (PD) is one of the most common forms of neurodegenerative diseases and research on potential therapeutic agents for PD continues. Rotenone is a neurotoxin that can pass the blood-brain barrier and is used to generate PD models in experimental animals. Boron is a microelement necessary for neural activity in the brain. Antioxidant, non-cytotoxic, anti-genotoxic, anti-carcinogenic effects of boric acid, the salt compound of boron has been reported before. Boronic acids have been approved for treatment by FDA and are included in drug discovery studies and pyridine boronic acids are a subclass of heterocyclic boronic acids used in drug design and discovery as substituted pyridines based on crystal engineering principles. The aim of our study was to determine the effect of 3-pyridinylboronic acid in rotenone-exposed zebrafish embryos, focusing on oxidant-antioxidant parameters and gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes gclm, gclc, hmox1a, nqo1, and PD related genes, brain-derived neurotrophic factor, dj1, and tnfα. Zebrafish embryos were exposed to Rotenone (10 μg/l); Low Dose 3-Pyridinylboronic acid (100 μM); High Dose 3-Pyridinylboronic acid (200 μM); Rotenone + Low Dose-3-Pyridinylboronic acid (10 μg/l + 100 μM); Rotenone + High Dose-3-Pyridinylboronic acid (10 μg/l + 200 μM) in well plates for 96 h post-fertilization (hpf). Our study showed for the first time that 3-pyridinylboronic acid, as a novel sub-class of the heterocyclic boronic acid compound, improved locomotor activities, ameliorated oxidant-antioxidant status by decreasing LPO and NO levels, and normalized the expressions of bdnf, dj1, tnf⍺ and Nrf2 target genes hmox1a and nqo1 in rotenone exposed zebrafish embryos. On the other hand, it caused the deterioration of the oxidant-antioxidant balance in the control group through increased lipid peroxidation, nitric oxide levels, and decreased antioxidant enzymes. We believe that these results should be interpreted in the context of the dose-toxicity and benefit-harm relationship of the effects of 3-pyridinylboronic.

Synthesis of a Bcl9 Alpha-Helix Mimetic for Inhibition of PPIs by a Combination of Electrooxidative Phenol Coupling and Pd-Catalyzed Cross Coupling

Teraryl-based alpha-helix mimetics have resulted in efficient inhibitors of protein-protein interactions (PPIs). Extending the concept to even longer oligoarene systems would allow for the mimicking of even larger interaction sites. We present a highly efficient synthetic modular access to quateraryl alpha-helix mimetics, in which, at first, two phenols undergo electrooxidative dehydrogenative cross-coupling. The resulting 4,4′-biphenol is then activated by conversion to nonaflates, which serve as leaving groups for iterative Pd-catalyzed Suzuki-cross-coupling reactions with suitably substituted pyridine boronic acids. This work, for the first time, demonstrates the synthetic efficiency of using both electroorganic as well as transition-metal catalyzed cross-coupling in the assembly of oligoarene structures.

Cations brought together by hydrogen bonds: the protonated pyridine-boronic acid dimer explained.

According to the Cambridge Structural Database, protonated pyridine-boronic acid dimers exist in the solid phase, apparently defying repulsive coulombic forces. In order to understand why these cation-cation systems are stable, we carried out M06-2X/6-311++G(3df,2pd) electronic structure calculations and used a set of computational tools (energy partitioning, topology of the electron density and electric field maps). The behavior of the charged dimers was compared with the corresponding neutral systems, and the effect of counterions (Br- and BF4-) and the solvent (PCM model) on the binding energies has been considered. In the gas-phase, the charged dimers present positive binding energies but are local minima, with a barrier (16-19 kJ mol-1) preventing dissociation. Once the environment is included via solvent effects or counterions, the binding energies become negative; remarkably, the strength of the interaction is very similar in both neutral and charged systems when a polar solvent is considered. Essentially, all methods used evidence that the intermolecular region where the HBs take place is very similar for both neutral and charged dimers. The energy partitioning explains that repulsion and electrostatic terms are compensated by the desolvation and exchange terms in polar solvents, thus giving stability to the charged dimer.

Pyridine boronic acid-polyoxometalate based porous hybrid for efficient depletion of high abundant glycoproteins in plasma.

A porous hybrid, namely PW12@TiO2-Si(Et)Si/Pba, is fabricated by the modification of PW12@TiO2-Si(Et)Si with pyridine boronic acid via a solvothermal method. The covalent interactions between the boronic acid group of the hybrid and the glycosylated site of proteins provide the as-prepared hybrid with favorable adsorption performance towards glycoproteins. The adsorption behaviors of glycoproteins onto the hybrid fit well with the Langmuir model, and the adsorption capacities for glycoprotein IgG and Trf are high, up to 348.5 mg g-1 and 262.6 mg g-1, respectively. Thus, a protocol for the depletion of high abundant glycoproteins from human plasma is proposed. The percentage contents of Trf, IgG, haptoglobinis and IgM are reduced from 7.38%, 5.5%, 3.01% and 1.02% to 0.951%, 4.7%, 0.126% and 0.76%, respectively. 85 low abundant proteins are identified from the raw plasma after the depletion of the high abundance proteins, demonstrating the potential of PW12@TiO2-Si(Et)Si/Pba hybrid in proteomic studies.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

Using asymmetric catalysis to simultaneously form carbon–carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib—an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.

Supramolecular networks in molecular complexes of pyridine boronic acids and polycarboxylic acids: synthesis, structural characterization and fluorescence properties

3- and 4-pyridineboronic acids have been combined with trimesic and pyromellitic acids to give three molecular complexes.

Electrochemical Molecular Recognition System Utilizing Current Amplification of Metal Complexes Assembled on Gold Nanoparticles

Introduction Because gold nanoparticles (GNP) have a characteristic color and the color changes by their aggregation, the optical molecular recognitions are widely investigated by using a color change. However, we reported that the electrochemical sugar recognition system using tris(acetylacetonato)ruthenium complex and boronic acid assembled on the GNP showed a glucose-selectivity and higher sensitivity in 10-6 M order than optical recognition.1) It is considered that one of the reasons of high sensitivity may be the amplification of the reduction current of tris(acetylacetonato)ruthenium complex by assembly on the GNP. This electrochemical molecular recognition system has a great advantage that the molecular recognition site can exchange to others according to the target molecules. Furthermore, the metal complex can also change to the others according to avoid the disturbance from coexistent redox active species. That is, the redox potential can select by changing the redox active complex. Purpose For the purpose of the verification of the current amplification and the utility of this electrochemical molecular recognition system using the GNP, in this work, ferrocene (Fc), tris(acetylacetonato)ruthenium ([Ru(acac)3]), bis(acetylacetonato)ruthenium ([Ru(acac)(BP)2], BP = pyridine boronic acid), and bipylidine ruthenium ([Ru(py)(bpy)(trpy)]) were assembled on the GNP as electroactive site. Boronic acid (BA) for recognition of sugar, dipicolilamine (DPY) for recognition of phosphate derivatives (ADP, ATP, etc.), succinimide (SCI) for recognition of dopamine (DA), and crown ether (CE) for recognition of cesium ion were assembled on the GNP. Thus, the six kinds of GNP complexes (GNP/[Ru(acac)(BP)2]/BA, GNP/Fc/BA, GNP/[Ru(py)(bpy)(trpy)]/BA, GNP/[Ru(acac)3]/DPY, GNP/[Ru(acac)3]/CE), and GNP/[Ru(acac)3]/SCI) prepared and investigated molecular recognition functions. Osteryoung square wave voltammetry (OSWV) or differential pulse voltammetry (DPV) were used for the electrochemical measurements. Results 1. Current Amplification: In order to confirm the current amplification, the concentration dependence of the reduction current of the [Ru(acac)3] and of GNP/[Ru(acac)3] were measured and their slopes were compared. The slope for GNP/[Ru(acac)3] was ca. 29 times larger than that for [Ru(acac)3]. For oxidation current of ferrocene, the slope for GNP/Fc was ca. 7 times larger than that for Fc. In the silver nanoparticle system, further current amplification was observed, so it is considered that the kind of nanoparticle seem to affect the current amplification. The mechanism of the current amplification is not yet clear, but the electron tunneling due to the electron conductivity of the GNP may be considered as main factor of the current amplification mechanism.2. Molecular Recognition: In the electrochemical measurement, the current values decreased by adding the target molecules. In the case of sugar recognition by BA, GNP/[Ru(acac)3]/BA showed highest sensitivity among three types of GNP complexes (GNP/[Ru(acac)3]/BA, GNP/Fc/BA, and GNP/[Ru(py)(bpy)(trpy)]/BA). Sensitivity of [Ru(py)(bpy)(trpy)] was slightly less than two metal complexes. Each complex showed different selectivity for three kinds of sugars. For GNP/[Ru(acac)(BP)2]/BAsystem (recognition site (BP) is on the Ru complex), sensitivity is higher than that of GNP/[Ru(acac)3]/BA, although the selectivity did not show for three kinds of sugar. GNP/[Ru(acac)3]/(DPY+Zn2+) could be recognized phosphate derivatives such as AMP, ADP, and ATP with high sensitivity (10-6 M order) in the presence of Zn2+. Furthermore, slight ATP selectivity was obtained. GNP/[Ru(acac)3]/CE showed an excellent sensitivity for cesium ion (10-9 M order). In this case, it was consider that the aggregation caused by CE ring sandwiching for cesium ion increased the sensitivity, because the CE (18-crown-6) ring size was smaller than cesium ion diameter. In this case, two types of GNP (type A and type B) complexes were prepared. In type A, CE probe has longer alkyl chain than [Ru(acac)3] probe, and in type B CE probe has same length as [Ru(acac)3] probe. Type A may aggregate more than type B, because there is no steric obstruction by [Ru(acac)3]. As a result, the detection limit of the type A is 0.4 nM and 10 times as sensitive as type B. For the recognition of dopamine, the aggregation of GNP is brought about by the complexation of dopamine in the presence of Fe3+. As a result, high sensitivity was attained (LOD = 3 nmol dm-3).By using this electrochemical molecular recognition system, target molecules could be recognized with high sensitivity of mM – nM. The sensitivity and selectivity was depending on the kind of electroactive metal complex. Thus, it was verified the utility of this electrochemical molecular recognition system using metal complexes assembled on gold nanoparticles. 1) A.Endo, M. Kimura, T. Hashimoto, and T. Hayashita, Anal. Methods, 2014, 6(22), 8874-8877. Figure 1

ChemInform Abstract: An Alkyne Diboration/6π‐Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives.

AbstractThe novel diboration/6π‐electrocyclization strategy enables rapid access to bicyclic pyridines, although the suitability of this method to access monocyclic heterocycles will likely require further method development.

An Alkyne Diboration/6π-Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives.

A new and efficient synthesis of pyridine-based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π-electrocyclization strategy. This method delivers a range of functionalized heterocycles from readily available starting materials.

An Alkyne Diboration/6π‐Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives

AbstractA new and efficient synthesis of pyridine‐based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π‐electrocyclization strategy. This method delivers a range of functionalized heterocycles from readily available starting materials.

Fluorescence probe for monosaccharide based on anionic polyelectrolyte and cationic pyridine quaternary ammonium salt

A facile fluorescence switch for monosaccharides is comprised of anionic polyelectrolyte and cationic trispyridine quaternary ammonium salt. In the switch ensemble, the polyelectrolyte was used as a fluorescent signal unit, and the pyridine boronic acid acted as receptor and quencher. The probe for monosaccharides detection shows a reversible “on-off” fluorescence response based on electrostatic interaction mechanism. This probe can be applied to detect diabetes only using a little blood sample. Moreover, the design idea and detection way may provide a new mode for diabetes diagnosis with high sensitivity.

Reversible “off–on” fluorescent probe for anions based on a facile two-component ensemble

Abstract A specific fluorescent switch for anions was successfully constructed. The novel sensing switch is a two-component ensemble, which was combined using a water-soluble conjugated polyelectrolyte and a boronic acid functionalized pyridine salt. In the ensemble, the polyelectrolyte is used as a fluorescent signal unit, and the pyridine boronic acid acts as receptor and quencher. The two-component ensemble shows a fluorescence reversible “off–on” response toward cyanide and phosphate anions based on different binding ways. Furthermore, the facile design and construction of this ensemble presents a novel opportunity for obtaining an efficient and practical probe.

Pyridine boronic acids as building blocks in crystal engineering

C357 describe two new families of layered silver carboxylates in which the interlayer region is more highly fluorinated. The first series, of general formula {Ag(CF3(CF2)nCO2)Q} , where n = 0-3, Q = quinoxalene, projects fluoroalkyl chains into the interlayer region. A family of compounds has been characterised in which interlayer spacing can be controlled. The second series employs fluoroaromatic groups through coordination of the pentafluorophenylacetate ion, C6F5CH2CO2.

A colorimetric titration method for quantification of millimolar glucose in a pH 7.4 aqueous phosphate buffer

3-Pyridinylboronic acid is identified as a key sensing element for reversible sugar complexation in an aqueous solution at the physiological pH. The utility of a sensing element has been demonstrated through a simple colorimetric titration of glucose using absorption spectroscopy in the visible region. The mechanism of the high diol/triol binding affinity of pyridine boronic acid in the neutral pH is discussed based on the 1H and 11B NMR spectroscopic studies.

Efficient Synthesis of a GABAA α2,3-Selective Allosteric Modulator via a Sequential Pd-Catalyzed Cross-Coupling Approach

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.