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Results for “Boronic Acids”

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PubMed1982

Inhibition of lipoprotein lipase by benzene boronic acid. Effect of apolipoprotein C-II.

The catalytic mechanism of triacylglycerol hydrolysis by lipoprotein lipase was studied. We found lipoprotein lipase to be inhibited by benzene boronic acid, with an apparent Ki of 8.9 micro M at pH 7.4. This indicates the presence of serine and histidine in the active site of the enzyme. Inhibition of lipoprotein lipase by benzene boronic acid is likely to be due to the formation of an inhibitor-enzyme complex having analogous bonding to the active site histidine and serine as the transition-state complex which precedes the formation of an obligatory acyl-enzyme intermediate. The presence of apolipoprotein C-II, the apolipoprotein activator of lipoprotein lipase, partly reverses the inhibition of lipoprotein lipase by benzene boronic acid. This reversal by apolipoprotein C-II has a distinct pH optimum in the range of 8-9.

Animals↗
PubMed2001

Highly fructose selective transport promoted by boronic acids based on a pentaerythritol core.

We have designed and synthesized a highly lipophilic boronic acid (11) with a molecular shape that makes it much more effective at carrying sugars through organic membranes than a previously used steroidal boronic acid. The corresponding diboronic acid (12) was also found to transport fructose ahead of glucose with a very high selectivity (7.6:1.0). Modeling suggests that 12 is able to carry two fructose molecules at once in a complex stabilized through hydrogen bonding and ion pairing.

Boronic Acids↗
PubMed2006

First study of metal hybrids of boronic acids: second-sphere coordination networks in the structures of 4-carboxyphenylboronic acid with some transition metals.

Metal-organic hybrids of a boronic acid (4-carboxylphenylboronic acid) with Co(II), Mn(II), and Ni(II) salts have been reported for the first time. In all of the complexes, there is no interaction between the metal and boronic acid through dative bonds. Furthermore, second-sphere coordination, along with water clusters in the form of octamers, was observed in the absence of any other additional ligands. However, in the presence of aza-donor molecules such as 1,2-bis(4-pyridyl)ethane, metal ions formed coordination polymers with those ligands, replacing the second-sphere coordination.

Journal Article↗
PubMed2005

Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.

Targeting the microtubule system represents an attractive strategy for the development of anticancer agents. In this study, we report a class of combretastatin A-4 (CA-4) analogs derivatized with a boronic acid moiety replacing the hydroxyl group on the C-ring of CA-4. Docking studies of the X-ray structures of our aryl-boronic analogs onto an X-ray structure of the alpha,beta-tubulin heterodimer suggested that cis-6 was a potent inhibitor of the colchicine binding. The model indicated that there would be strong hydrogen bonding between the boronic acid moiety and Thr-179 and Val-181 of alpha-tubulin. We demonstrate that the cis-6 boronic acid bioisostere of CA-4: (1) inhibits tubulin assembly, (2) competitively displaces colchicine, and (3) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Aza-boronic acids as non-beta-lactam inhibitors of AmpC-beta-lactamase.

With the aim of improving the ability of non-beta-lactam inhibitors to inhibit AmpC-beta-lactamase, a series of 3-aza-phenyl-boronic acid derivatives was obtained using in parallel synthesis. The molecules were tested against Escherichia coli AmpC-beta-lactamase. The best inhibitors, 3-(2-hydroxy-naphthalen-1-ylazo)-phenyl-boronic acid (12) and 3-(2,4-dihydroxy-naphthalen-1-ylazo)-phenyl-boronic acid (14), showed apparent inhibition constant values (K(i)) of 0.3 and 0.45 microM and increased the potency of the semi-synthetic cephalosporin antibiotic, ceftazidime, lowering its minimum inhibitory concentration (MIC) value of 50%, against Gram-negative bacteria strains, producing high levels of AmpC-beta-lactamase.

Aza Compounds↗
PubMed2000

Thiol ester-boronic acid cross-coupling. Catalysis using alkylative activation of the palladium thiolate intermediate.

Thiol esters and boronic acids do not participate in cross-coupling in the presence of palladium catalysts. However, efficient palladium-catalyzed thiol ester-boronic acid cross-coupling is observed when simple alkylating agents are present. Alkylative conversion of the very stable palladium-thiolate bond to a labile palladium-thioether bond is presumed to be crucial to the catalysis. Of the systems studied, 4-halo-n-butyl thiol esters were most effective in this cross-coupling.

Alkylation↗
PubMed1995

Selective extraction of quercetrin in vegetable drugs and urine by off-line coupling of boronic acid affinity chromatography and high-performance liquid chromatography.

Quercetrin, quercetin and chlorogenic acid were measured in urine or in drugs by combination of boronic acid affinity chromatography and HPLC. Simple reversed-phase HPLC with UV detection was used to determine quercetrin in five different Solidago virgaurea drugs. For determination of quercetrin in human urine immobilized boronic acid was applied for sample pretreatment. this procedure leads to a determination limit of 0.01 micrograms/ml with a recovery rate of 95.3%. The first results using this method for quercetrin pharmacokinetics are presented.

Boronic Acids↗
PubMed1995

NMR studies of the alpha-chymotrypsin-(R)-1-acetamido-2-(4-fluorophenyl)ethane-1-boronic acid complex at pH 7.

The interaction of (R)-1-acetamido-2-(4-fluorophenyl)ethane-1-boronic acid with alpha-chymotrypsin at pH 7 was studied by a variety of fluorine and proton NMR experiments and the results compared to observations made at pH 4. It was demonstrated that this compound forms a complex with a 1:1 stoichiometry at pH 7; proton NMR indicates that the boronic acid likely is coordinated to the serine-195 residue at the active site. Analysis of fluorine T1 relaxation behavior and 19F(1H) NOE data shows that the rate constant for dissociation of the complex is 4.7 s-1, somewhat faster than is observed at pH 4. The data analysis and the results of two-dimensional 19F(1H) NOE experiments show that interactions between the fluoroaromatic ring of the inhibitor and the enzyme are weaker at the higher pH value, although the motion of the fluoroaromatic ring within the complex appears to be just as restricted as is the case at pH 4.

Boronic Acids↗
PubMed2006

Water-soluble fluorescent boronic acid compounds for saccharide sensing: substituent effects on their fluorescence properties.

Four new naphthalene-based boronic acid compounds (1-4) were synthesized. The effect of various carbohydrates on their fluorescence properties has been studied in aqueous phosphate buffer at pH 7.4. Different substitutions on the aniline group of the naphthalene ring resulted in significant differences in fluorescence properties for these four compounds. Compound 1 shows ratiometric fluorescence changes upon addition of a sugar. Compounds 2 and 3 do not show ratiometric fluorescence changes but show very large fluorescence intensity changes (about 70-fold fluorescence intensity increase). In addition to the quantifiable fluorescence property changes upon sugar addition, the fluorescence color changes of 1-3 are also visible to the naked eye. However, amidation of the aniline nitrogen atom significantly diminishes the fluorescence intensity of compound 4. The crystal structure of one boronic acid provided some insight into the structural features that are important for the fluorescence properties of these compounds.

Biosensing Techniques↗
PubMed2004

Regulating the fluorescence intensity of an anthracene boronic acid system: a B-N bond or a hydrolysis mechanism?

An anthracene-based fluorescent boronic acid system developed by the Shinkai group has been widely used for the preparation of fluorescent sensors for carbohydrates. Such application is based on the significant fluorescence intensity increase of this system upon binding with a carbohydrate. The mechanism through which this fluorescence intensity change happens was originally proposed to go through a B-N bond formation mechanism, which masks the nitrogen lone pair electrons. However, our own fluorescence studies suggest a possible alternative mechanism for the fluorescence change upon the formation of a boronic acid (1a) complex with diols. In this new proposed mechanism, complex formation induces solvolysis, which results in the protonation of the amine nitrogen if the reactions are carried out in a protic solvent such as water. This protonation prevents the photoinduced electron transfer, resulting in reduced quenching of the anthracene fluorescence. Such a solvolysis mechanism is supported by evidence from various types of experiments and theoretical calculations.

Anthracenes↗
PubMed2000

Characterization of peptidyl boronic acid inhibitors of mammalian 20 S and 26 S proteasomes and their inhibition of proteasomes in cultured cells.

Proteasomes are large multisubunit proteinases which have several distinct catalytic sites. In this study a series of di- and tri-peptidyl boronic acids have been tested on the chymotrypsin-like activity of purified mammalian 20 S and 26 S proteasomes assayed with succinyl-Leu-Leu-Val-Tyr-amidomethylcoumarin (suc-Leu-Leu-Val-Tyr-AMC) as substrate. The inhibition of 20 S proteasomes is competitive but only slowly reversible. The K(i) values for the best inhibitors were in the range 10-100 nM with suc-Leu-Leu-Val-Tyr-AMC as substrate, but the compounds tested were much less effective on other proteasome activities measured with other substrates. Free boronic acid inhibitors exhibited equivalent potency to their pinacol esters. Both benzoyl (Bz)-Phe-boroLeu and benzyloxycarbonyl (Cbz)-Leu-Leu-boroLeu pinacol ester inhibited 20 S and 26 S proteasomes with non-ideal behaviour, differences in inhibition of the two forms of proteasomes becoming apparent at high inhibitor concentrations (above 3xK(i)). Both of these compounds were also potent inhibitors of 20 S and 26 S proteasomes in cultured cells. However, gel filtration of cell extracts prepared from cells treated with radiolabelled phenacetyl-Leu-Leu-boroLeu showed that only 20 S proteasomes were strongly labelled, demonstrating differences in the characteristics of inhibition of 20 S and 26 S proteasomes. The usefulness of peptidyl boronic acid inhibitors for investigations of proteasome-mediated protein degradation was confirmed by the observation that Bz-Phe-boroLeu and Cbz-Leu-Leu-boroLeu pinacol ester inhibited NFkappaB activation with IC(50) values comparable to their K(i) values for purified proteasomes. The latter result supports the view that the chymotrypsin-like activity of proteasomes assayed with suc-Leu-Leu-Val-Tyr-AMC is a critical one for protein degradation in cells.

Animals↗
PubMed2001

Boronic acid fluorophore/beta-cyclodextrin complex sensors for selective sugar recognition in water.

A novel boronic acid fluorophore 1/beta-cyclodextrin (beta-CyD) complex sensor for sugar recognition in water has been designed. The probe 1 bearing pyrene moiety as a fluorescent signal transducer exhibits no fluorescence emission, due to its aggregation in water containing 2% DMSO; however, the addition of beta-CyD to this solution largely changes UV-vis and fluorescence spectra of 1 by forming an inclusion complex with beta-CyD, and an efficient fluorescence emission response of 1/beta-CyD complex upon sugar binding is found to be obtained at pH 7.5. The pH-fluorescence profile of the 1/beta-CyD complex reveals that the boronate ester formation with fructose induces the apparent pKa shift from 7.95+/-0.03 in the absence of fructose to 6.06+/-0.03 in the presence of 30 mM fructose, resulting in the fluorescence emission response under the neutral condition. The spectral properties of 1 in 95% methanol:5% water (v/v), as well as the fluorescence quenching study of 1-methylpyrene with 4-methoxycarbonylphenyl-boronic acid 2, demonstrate that the response mechanism is based on the photoinduced electron transfer (PET) from the pyrene donor to the acid form of phenylboronic acid acceptor in 1, and thus, the proton dissociation of phenylboronic acid induced by sugar binding inhibits the PET system while increasing the fluorescence intensity of the pyrene moiety. To evaluate the binding ability and selectivity of the 1/beta-CyD complex for monosaccharides in water, the response equilibria have been derived. The 1:1 binding constants of the 1/beta-CyD complex obtained from the equilibrium analysis are in the order: D-fructose (2515+/-134 M(-1)) >> L-arabinose (269 +/- 28 M(-1)) > D-galactose (197+/-28 M(-1)) > D-glucose (79+/-33 M(-1)), which is consistent with the binding selectivity of phenylboronic acid.

Journal Article↗
PubMed2001

Synthesis of boronic acid analogues of alpha-amino acids by introducing side chains as electrophiles.

A synthetic route has been developed which has allowed us to prepare novel alpha-aminoboronic acids as inhibitors of serine proteases. These compounds were prepared to study the roles of proteases in biological systems. This methodology affords alpha-aminoboronic acids with the general formula R'-NHCH(R)BO(2)-pinanediol, where R = -CH(2)CHF(2), -CH(2)CO(2)tBu, and -(CH(2))(2)CO(2)Me and R' = either H or C(O)R". The latter two compounds are the boronic acid analogues of the natural amino acids aspartic acid and glutamic acid with the side chain carboxylate protected as a tert-butyl or a methyl ester, respectively. Following acylation of the amino group, the side chain tert-butyl ester of boroaspartic acid was removed by treatment with TFA. Boroglutamic acid was obtained as the free boronic acid by hydrolysis with HCl. Prior syntheses of alpha-aminoboronic acids involve the initial addition of an organometallic reagent to a trialkyl borate ester. These conditions do not allow the preparation of compounds with functionalities that are not stable to the strongly basic reaction conditions. The methodology described here allows the preparation of alpha-aminoboronic acids by introducing side chains as electrophiles. This is particularly advantageous for side chains which are prone to elimination or unwanted enolate formation. Specifically, BrCH(2)CHF(2), BrCH(2)COO(t)Bu, and CH(2)=CHCOOMe were allowed to react with the stabilized anion of (phenylthio)methane boronate, PhSCH(2)BO(2)C(6)H(12), to give the substituted boronate. The substituted (phenylthio)methane boronate was converted to the corresponding sulfonium ion by treatment with methyl iodide and subsequently displaced with iodide. The alpha-iodo derivative was converted to the amine by conventional methods.

Amino Acids↗
PubMed1984

Serum cholinesterase inhibition by boronic acids.

Horse serum cholinesterase (acylcholine acylhydrolase, EC 3.1.1.8) was reversibly inhibited by a variety of alkyl- and areneboronic acids with Ki values ranging from 6.2 mM (methaneboronic acid) to 3.1 microM (diphenylboric acid). Binding to the enzyme was apparently at the active center, because inhibition obeyed competitive kinetics and because boronic acids protected the enzyme from inactivation by phenylmethanesulfonyl fluoride. Boronic acids should prove useful in probing the active center of serum cholinesterase.

Animals↗
PubMed2003

Unprecedented palladium-catalyzed cross-coupling reaction of alpha-bromo sulfoxides with boronic acids.

[reaction: see text] A new Suzuki-type palladium-catalyzed reaction of boronic acids with alpha-bromo sulfoxides has been developed using a protocol similar to the well-documented reaction of boronic acids with aryl halides. Both cross-coupling and homocoupling processes were observed. The best yields in cross-coupling products were obtained when the presence of oxygen was carefully excluded using degassed solvents. The oxidative addition palladium complex intermediate could be isolated and characterized by X-ray single-crystal diffraction.

Journal Article↗