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PubMed2004

A highly efficient microwave-assisted suzuki coupling reaction of aryl perfluorooctylsulfonates with boronic acids.

[reaction: see text] A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acids to form biaryls under general microwave conditions. Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel. Application of this tagging strategy to multistep synthesis of biaryl-substituted hydantoin is also described.

Alkanesulfonic Acids↗
PubMed2002

Nucleotide adsorption-desorption behaviour of boronic acid functionalized uniform-porous particles.

In this study, nucleotide adsorption-desorption behaviour of boronic acid-carrying uniform, porous particles was investigated. The particles were produced by a "multi-step microsuspension polymerization" in the form of poly(styrene-vinylphenyl boronic acid-divinylbenzene) terpolymer. In the first step of the production method, uniform polystyrene latex particles (6.2 microm in size) were obtained by dispersion polymerization. These particles were first swollen by a low molecular mass organic agent (i.e. dibutylphthalate, DBP) and then by a monomer mixture including styrene (S), 4-vinylphenyl boronic acid (VPBA) and divinylbenzene (DVB). The particle uniformity was protected in both swelling stages by adjusting DBP/polystyrene latex and monomer mixture/polystyrene latex ratios. Polymerization of the monomer mixture in the swollen seed particles provided boronic acid-carrying uniform, porous particles 11-12 microm in size. To have uniform particles with different porosities and boronic acid contents, the feed concentration of boronic acid-carrying monomer and the monomer/seed latex ratio were changed. The particles were tried as sorbent for the adsorption of a model nucleotide (i.e., beta-nicotinamide adenine dinucleotide, beta-NAD). In the beta-NAD adsorption experiments, the maximum equilibrium adsorption was obtained at pH 8.5 which was very close to pKa of boronic acid. The incorporation of boronic acid functionality provided a significant increase in the beta-NAD adsorption. In contrast to plain poly(styrene-co-divinylbenzene) particles, four-fold higher beta-NAD adsorption was obtained with the boronic acid functionalized particles. Beta-NAD was desorbed from the particles with the yields higher than 90% by weight.

Adsorption↗
PubMed2006

Buildup of gold nanoparticle multilayer thin films based on the covalent-bonding interaction between boronic acids and polyols.

A novel method for the fabrication of gold nanoparticle multilayer films based on the covalent-bonding interaction between boronic acid and polyols, poly(vinyl alcohol) (PVA), was developed. The multilayer buildup was monitored by UV-vis absorbance spectroscopy, which showed a linear increase of the film absorbance with the number of adsorbed Au layers and indicated the stepwise and uniform assembling process. The atomic force microscopy (AFM) image showed that a compact gold multilayer thin film was successfully assembled. The residual boronic acid group on the surface of thin film could incorporate glycosylated-protein horseradish peroxidase (HRP), and good catalytic activity for H2O2 could be observed.

Boronic Acids↗
PubMed1987

Serine protease mechanism: structure of an inhibitory complex of alpha-lytic protease and a tightly bound peptide boronic acid.

The structure of the complex formed between alpha-lytic protease, a serine protease secreted by Lysobacter enzymogenes, and N-tert-butyloxycarbonylalanylprolylvaline boronic acid (Ki = 0.35 nM) has been studied by X-ray crystallography to a resolution of 2.0 A. The active-site serine forms a covalent, nearly tetrahedral adduct with the boronic acid moiety of the inhibitor. The complex is stabilized by seven hydrogen bonds between the enzyme and inhibitor with additional stabilization arising from van der Waals interactions between enzyme and inhibitor side chains and the burying of 330 A2 of hydrophobic surface area. Hydrogen bonding between Asp-102 and His-57 remains intact in the enzyme-inhibitor complex, and His N epsilon 2 is well positioned to donate its hydrogen to the leaving group. Little change in the positions of protease residues was observed on complex formation (root mean square main chain deviation = 0.13 A), suggesting that in its native state the enzyme is complementary to tetrahedral reaction intermediates or to the nearly tetrahedral transition state for the reaction.

Boronic Acids↗
PubMed2003

2-(6-bromopyridin-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (6-bromopyridin-3-yl)boronic acid, new bifunctional building blocks for combinatorial chemistry.

The first comparative study between two new heterocyclic boron derivatives, viz. a (6-bromopyridin-3-yl)boronic ester, C(11)H(15)BBrNO(2), and (6-bromopyridin-3-yl)boronic acid, C(5)H(5)BBrNO(2), shows a small but not significant difference in their C-B bond lengths, which cannot explain the experimentally observed difference in their stabilities. The crystal packing of the boronic ester consists principally of van der Waals interactions, while the boronic acid molecules interact in their crystal through hydrogen bonds.

Journal Article↗
PubMed1989

(1-Aminoethyl)boronic acid: a novel inhibitor for Bacillus stearothermophilus alanine racemase and Salmonella typhimurium D-alanine:D-alanine ligase (ADP-forming).

(1-Aminoethyl)boronic acid (Ala-B), an analogue of alanine in which a boronic acid group replaces the carboxyl group, has been synthesized and found to inhibit the first two enzymes, alanine racemase (from Bacillus stearothermophilus, EC 5.1.1.1) and D-alanine:D-alanine ligase (ADP-forming) (from Salmonella typhimurium, EC 6.3.2.4), of the D-alanine branch of bacterial peptidoglycan biosynthesis. In both cases, time-dependent, slow binding inhibition is observed due to the generation of long-lived, slowly dissociating complexes. Ala-B inhibits alanine racemase with a Ki of 20 mM and a kappa inact of 0.15-0.35 min-1. Time-dependent loss of activity is paralleled by conversion of the 420-nm chromophore of initial bound PLP aldimine to a 324-nm absorbing species. On dilution of Ala-B, racemase activity is regained with a t1/2 of ca. 1 h. The D-Ala-D-Ala ligase also shows progressive inhibition by Ala-B provided ATP (but not AMP-PNP or AMP-PCP) is present. The presence of D-alanine along with ATP also leads to Ala-B-induced inactivation. Kinetic analysis suggests Ala-B can compete with D-alanine at either of the two D-alanine binding sites, and on inactivation with Ala-B, labeled D-alanine, and labeled ATP, the inactive enzyme has stoichiometric amounts of D-alanine, ADP, Pi, and Ala-B bound. The half-life of inactive enzyme complexes varied from approximately 2 h (without D-alanine) to 4.5 days (with D-alanine). No D-Ala-D-Ala-B dipeptide was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2006

Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction.

Bortezomib (1) is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor employed in the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. The potency of 1 is owed primarily to the presence of the boronic acid moiety, one which is suited to establish a tetrahedral intermediate with the active site N-terminal threonine residue of the proteasome. Hence, deboronation of 1 represents a deactivation pathway for this chemotherapeutic agent. Deboronation of 1 affords a near equal mixture of diastereomeric carbinolamide metabolites (M1/M2) and represents the principal metabolic pathway observed in humans. In vitro results from human liver microsomes and human cDNA-expressed cytochrome P450 enzymes (P450) indicate a role for P450 in the deboronation of 1. Use of 18O-labeled oxygen under controlled atmospheres confirmed an oxidative mechanism in the P450-mediated deboronation of 1, as 18O was found incorporated in both M1 and M2. Chemically generated reactive oxygen species (ROS), such as those generated as byproducts during P450 catalysis, were also found to deboronate 1 resulting in the formation of M1 and M2. Known to undergo efficient redox cycling, P450 2E1 was found to catalyze the deboronation of 1 predominantly to the carbinolamide metabolites M1 and M2, as well as to a pair of peroxycarbinolamides, 2 and 3. The presence of superoxide dismutase (SOD) and catalase prevented the deboronation of 1, thus, supporting the involvement of ROS in the P450 2E1-catalyzed deboronation reaction. The presence of SOD and catalase also protected 1 against P450 3A4-catalyzed deboronation, albeit to a lesser extent. The remaining deboronation activity observed in the P450 3A4 reaction may suggest the involvement of the more conventional activated enzyme-oxidants previously described for P450. Our present findings indicate that the oxidase activity of P450 (i.e., formation of ROS) represents a mechanism of deboronation.

Boranes↗
PubMed1990

Inhibition of IgA1 proteinases from Neisseria gonorrhoeae and Hemophilus influenzae by peptide prolyl boronic acids.

The alpha-aminoboronic acid analog of proline has been synthesized and incorporated into a number of peptides as the COOH-terminal residue. These peptide prolyl boronic acids are potent inhibitors of both the type 1 and type 2 IgA proteinases from Neisseria gonorrhoeae and Hemophilus influenzae, but not of the functionally similar IgA proteinase from Streptococcus sanguis. The best inhibitors synthesized thus far have Ki values in the nanomolar range (4.0 to 60 nM). These results indicate that the N. gonorrhoeae and the H. influenzae enzymes belong to the serine protease family of proteolytic enzymes while that from S. sanguis does not. As a group, the IgA proteinases have been noted for their remarkable specificity; thus, the peptide prolyl boronic acids reported here are the first small synthetic molecules to exhibit a relatively high affinity for the active site of an IgA proteinase and are therefore the first to yield some insight into the active site structure and specificity requirements of these enzymes.

Amino Acid Sequence↗
PubMed1998

Differences in binding modes of enantiomers of 1-acetamido boronic acid based protease inhibitors: crystal structures of gamma-chymotrypsin and subtilisin Carlsberg complexes.

In order to probe the structural basis of stereoselectivity in the serine protease family, a series of enantiomeric boronic acids RCH2CH(NHCOCH3)B(OH)2 has been synthesized and kinetically characterized as transition-state analog inhibitors using alpha-chymotrypsin and subtilisin Carlsberg as model systems. When the R-substituent in this series was changed from a p-chlorophenyl to a 1-naphthyl group, alpha-chymotrypsin, but not subtilisin, reversed its usual preference for l-enantiomers and bound more tightly to the D-enantiomer [Martichonok, V., & Jones, J. B. (1996) J. Am. Chem. Soc. 118, 950-958]. The structural factors responsible for the differences in stereoselectivity between the two enzymes have been explored by X-ray crystallographic examination of subtilisin Carlsberg and gamma-chymotrypsin complexes of the L- and D-enantiomers of p-chlorophenyl and 1-naphthyl boronic acid derivatives. In both enzymes, the L-isomers of the inhibitors, which are more closely related to the natural L-amino acid substrates, form tetrahedral adducts, covalently linking the central boron atom and Ogamma of the catalytic serine. The d-isomers, however, differ in the way they interact with subtilisin or gamma-chymotrypsin. With subtilisin, both the D-p-chlorophenyl and D-1-naphthyl inhibitor complexes form covalent Ser Ogamma-to-boron bonds, but with gamma-chymotrypsin, the same inhibitors lead to novel tetrahedral adducts covalently linking both Ser195 Ogamma and His57 Nepsilon2 covalently via the boron atom.

Binding Sites↗
PubMed2002

P1 Phenethyl peptide boronic acid inhibitors of HCV NS3 protease.

A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.

Antiviral Agents↗
PubMed1999

N,N-Diethanolaminomethyl Polystyrene: An Efficient Solid Support to Immobilize Boronic Acids.

The key to the efficiency of N,N-diethanolaminomethyl polystyrene (DEAM-PS), the first solid support capable of coupling to boronic acids, is the formation of a stable, resin-bound boronic ester ate adduct (see scheme). With this resin it is now possible to efficiently immobilize a wide variety of boronic acids including functionalized ones that can be derivatized by solid-phase combinatorial synthesis.

Journal Article↗
PubMed2002

Hepatitis C virus NS3 protease requires its NS4A cofactor peptide for optimal binding of a boronic acid inhibitor as shown by NMR.

NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic. In the absence of cofactor, the inhibitor had a lower affinity for the protease. Although the inhibitor binds in the same location, differences were observed at the catalytic site of the protease.

Binding Sites↗
PubMed1983

N-(5-dimethylaminonaphthalene-1-sulfonyl)-3-aminobenzene boronic acid as an active-site-directed fluorescent probe of lipoprotein lipase.

Resonance energy transfer was used to monitor the interaction of an active-site-directed fluorescent inhibitor, N-(5-dimethylaminonaphthalene-1-sulfonyl)-3-aminobenzene boronic acid, and lipoprotein lipase (EC 3.1.1.34). The binding of this probe to the active site of lipoprotein lipase had an association constant, Ka, of 1.1 X 10(6) M-1, indicating a strong interaction. The binding was displaced competitively by benzene boronic acid. The method described provides a sensitive procedure to probe the active site of lipoprotein lipase.

Animals↗
PubMed1985

UV-absorbance profile of human leukocytic ultrafiltrate after affinity chromatography on immobilized m-aminophenyl boronic acid: implication for transfer factor purification.

The UV-absorbance of the lysed human leukocyte ultrafiltrate (LLU) was investigated by Sephadex G-15 gel permeation chromatography before and after affinity chromatography on immobilized m-aminophenyl boronic acid. This biospecific fractionation caused substantial changes in 260/280-nm absorbance ratio of individual peaks as revealed by Sephadex G-15 gel permeation chromatography. While the material which had passed through the affinity support unretarded (W) appeared to be partly or completely deprived of peak IV, peaks IV and V were fairly enriched in the retarded material (R). This material, on the other hand, nearly completely missed peaks III, VI and VII. Peak III was copiously represented in material W. Boronate affinity chromatography caused enrichment in the protein content as well as in the content of purine/pyrimidine-bound ribose of material R, i.e. cis-diol group containing (RNA-like) material, considered to represent functional transfer factor activity. The described findings further support the use of immobilized derivatives of boronic acid in the separation of coplanar cis-diol group containing compounds from other constituents of LLU.

Boronic Acids↗
PubMed2001

Substituted alkyne synthesis under nonbasic conditions: copper carboxylate-mediated, palladium-catalyzed thioalkyne-boronic acid cross-coupling.

[figure: see text] A new methodology for the synthesis of substituted alkynes is described. In the presence of copper(I) thiophene-2-carboxylate (CuTC) or copper (I) 3-methylsalicylate (CuMeSal), the palladium-catalyzed cross-coupling of thioalkyne derivatives with boronic acids affords functionalized alkynes in yields ranging from 39 to 91%. This coupling occurs efficiently under mild, nonbasic conditions with a wide variety of thioalkynes and boronic acids, providing a reaction complementary to the Sonogashira protocol.

Alkynes↗
PubMed2002

Boronic acids: new coupling partners in room-temperature Suzuki reactions of alkyl bromides. Crystallographic characterization of an oxidative-addition adduct generated under remarkably mild conditions.

The Suzuki reaction is an exceptionally useful cross-coupling process that has been widely applied in synthetic chemistry, and boronic acids are, by far, the most commonly employed coupling partner. To date, however, no versatile method has been developed for cross-coupling boronic acids with unactivated alkyl (as opposed to aryl or vinyl) electrophiles. This report describes a catalyst system that achieves this objective at room temperature. On the mechanistic side, this study demonstrates that Pd(P(t-Bu)2Me)2 undergoes oxidative addition under surprisingly mild conditions (0 degrees C). The resulting adduct is sufficiently stable toward beta-hydride elimination that it can be structurally characterized, and it is a chemically competent intermediate in the cross-coupling process.

Boronic Acids↗
PubMed2004

Facile synthesis of 2-bromo-3-fluorobenzonitrile: an application and study of the halodeboronation of aryl boronic acids.

A scaleable synthesis of 2-bromo-3-fluorobenzonitrile via the NaOMe-catalyzed bromodeboronation of 2-cyano-6-fluorophenylboronic acid was developed. The generality of this transformation was demonstrated through the halodeboronation of a series of aryl boronic acids. Both aryl bromides and aryl chlorides were formed in good to excellent yields when the corresponding aryl boronic acid was treated with 1,3-dihalo-5,5-dimethylhydantoin and 5 mol % NaOMe.

Journal Article↗