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A range of aryl and heteroaryl boronic acids were tested for their in vitro hormone-sensitive lipase inhibitory properties. (2-Benzyloxy-5-fluorophenyl)boronic acid, (2-benzyloxy-5-chlorophenyl)boronic acid and 5-bromothiophene-2-boronic acid were found to be the most potent HSL inhibitors with IC(50) values of 140, 17 and 350 nM, respectively.
Three carboranyltetraphenylporphyrins containing 40 or 80 boron atoms were synthesized and evaluated for their biodistribution and toxicity in EMT-6 tumor-bearing mice. Copper (II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 6, and copper (II) meso-5,10,15,20-tetrakis[3-hydroxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 8, are B40 congeners with different lipophilicities, each less than their B80 congener, copper (II) meso-5,10,15,20-tetrakis[m-(3,5-di-o-carboranylmethoxybenzyloxy)phenyl]porphyrin, 18. Two days after the last of a series of i.p. injections in BALB/c mice bearing EMT-6 mammary tumors, a dose of 185 mg/kg 6 (54 mg/kg B) delivered over 3.5 times the concentration of boron to tumor (169 microg/g B) than did 118 mg/kg 8 (36 mg/kg B), which delivered 35 microg/g B, or 87 mg/kg 18 (30 mg/kg B), which delivered 46 microg/g B. The tumor-to-blood and tumor-to-brain boron concentration ratios at that time for all three porphyrins exceeded 80:1. Two days after the last injection, there resulted moderate thrombocytopenia that essentially disappeared two days later from 6 and 18, and mild leukocytosis from 6, 8, and 18, all of which were clinically inconsequential. Thus, 6 may rank among the most clinically promising carboranyl porphyrins ever made to deliver 10B to tumors for boron neutron-capture therapy (BNCT) that has also been tested for its toxicity in vivo.
Several boronic acids were screened for their ability to bind to diols. 3-methoxycarbonyl-5-nitrophenyl boronic acid bound to both a catechol dye as well as fructose with a comparable affinity to that of an ortho-methylamino substituted boronic acid. This work suggests a greater role for appropriately functionalized electron deficient boronic acids in diol and carbohydrate recognition.
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.
The application of a boronate precolumn in the trace determination of 4,4'-isopropylidenediphenol (bisphenol A or BPA) in aqueous solution was investigated by microcolumn liquid chromatography (LC). BPA was enriched by a precolumn packed with TSK(gel) boronate and it was then injected (back-flushed) into an ODS separation column. Comparing to a conventional syringe injection, a better peak shape was obtained via the boronate precolumn injection, and the calculated theoretical plate number improvement was approximately two folds. The relative standard deviations for the retention time, peak area and peak height were 0.12, 3.0 and 1.8%, respectively. The system is linear (R2>0.99) within the working sample concentration and sample-volume ranges, and it presents a detection limit of 0.09 microg L(-1)(S/N=3) when a 0.2 mL sample was enriched. Recovery values of the proposed method were between 107 and 123%, and this method was applied satisfactorily to the determination of BPA in commercially available bottled drink samples. The boronate precolumn was proven to produce better sensitivity than that of an ODS or C30 precolumn as long as the enrichment of BPA in aqueous samples is concerned.
In the present paper, boron removal from aqueous solutions by adsorption was investigated. Fly ash particle size used in adsorption experiments was between 250 and 400 microm. During the experimental part of this study, the effect of parameters such as pH, agitation time, initial boron concentration, temperature, adsorbent dosage and foreign ion on boron removal were observed. In addition, adsorption kinetics, adsorption isotherm studies and column studies were made. Maximum boron removal was obtained at pH 2 and 25 degrees C. Thermodynamic parameters such as change in free energy (DeltaG degrees), enthalpy (DeltaH degrees), entropy (DeltaS degrees) were also determined. As a result of the kinetic studies, it was observed that the adsorption data conforms to the second degree kinetics model. In the isotherm studies, Langmuir and Freundlich isotherm models were applied and it was determined that the experimental data conformed to Langmuir isotherm model. Batch adsorbent capacity (q(o)) was calculated as 20.9 mg/g. The capacity value for column study was obtained by graphical integration as 46.2 mg/g. The Thomas and the Yoon-Nelson models were applied to experimental data to predict the breakthrough curves and to determine the characteristics parameters of the column useful for process design.
A linear correlation between boron and organic carbon has been identified for groundwater and surface water. The boron to organic carbon ratio is found to be higher for groundwaters than for surface waters, since surface waters are more heavily loaded with natural organic matter. This correlation in water might result from the complexation of boron with polar organic compounds, not adsorbed on activated carbon, or from independent species. Any deviation from the boron/organic carbon ratio is used to identify pollution events for both boron or organic compounds, and to characterise the origin of unusual water chemistries. Moreover, such a correlation could be used to define natural water pristine conditions in order to restore good quality of water resources.
CHO cells were exposed to thermal neutrons and their mutation frequency was determined. The Kyoto University Research Reactor (KUR), which has a very low level of contamination by gamma-rays and fast neutrons was used as a thermal neutron source. Cells were irradiated in the presence or absence of boric acid to determine mutation frequency and cell survival. Thermal neutron irradiation was 2.5 times as mutagenic as gamma-irradiation without boron. In the presence of boron, however, thermal neutron irradiation was from 4.2 to 4.5 times as mutagenic as gamma-irradiation. When the mutation frequency was plotted against the survival fraction, a higher degree of mutagenicity was observed in the presence than in the absence of boron. These results suggest that the enhancement of thermal neutron-induced mutation with boron is strongly associated with alpha-particles released by 10B(n, alpha)7 Li reaction.
Boron implantation into Nitinol alloy has a potential for developing improved Nitinol root canal instruments with excellent cutting properties, without affecting their superelastic bulk-mechanical properties. The surface hardness of nickel-titanium (NiTi) alloy, also known as "Nitinol" (50 atm% nickel+50 atm% titanium), has been improved by ion-beam surface modification. With an implantation dose of 4.8 x 10(17) boron/cm2, a high concentration of boron (30 atm%) is incorporated into NiTi alloy by 110 keV boron ions at room temperature (25 degrees C). Boron-implanted and unimplanted (pure) Nitinol alloys show surface hardness of 7.6 +/- 0.2 and 3.2 +/- 0.2 GPa, respectively, at the nanoindentation depth of 0.05 micron. The ion-beam-modified NiTi alloy exceeds the surface hardness of stainless steel.
A variety of techniques and measurements on all NMR accessible nuclei allow one to obtain a complete and precise set of chemical shift and quadrupole coupling parameters for both boron and nitrogen in cubic and hexagonal boron nitride. For hexagonal boron nitride, 11B to 15N cross polarization under magic angle sample spinning conditions is demonstrated at natural isotope abundance. The presented approach for NMR characterization of the crystalline boron nitrides should also be applicable to structurally related composite materials, nanotubes, and amorphous ceramics.
Curcumin, a relatively non-toxic natural product isolated from Curcuma longa, is a modest inhibitor of the HIV-1 (IC50 = 100 microM) and HIV-2 (IC50 = 250 microM) proteases. Simple modifications of the curcumin structure raise the IC50 value but complexes of the central dihydroxy groups of curcumin with boron lower the IC50 to a value as low as 6 microM. The boron complexes are also time-dependent inactivators of the HIV proteases. The increased affinity of the boron complexes may reflect binding of the orthogonal domains of the inhibitor in interesecting sites within the substrate-binding cavity of the enzyme, while activation of the alpha, beta-unsaturated carbonyl group of curcumin by chelation to boron probably accounts for time-dependent inhibition of the enzyme.
Distinct biological properties of the ortho-carboranyl (1,2-dicarba-closo-dodecaboranyl) glycosides 1, 2 and 3 were evaluated to estimate the suitability of these compounds for cancer treatment by boron neutron capture therapy. The boron uptake into B16-Melanoma cells was significantly higher by incubating the cells with aqueous solutions of carboranyl glucoside 1 (11.2 ppm after 3h), lactoside 2 (13.2 ppm after 12h) and maltoside 3 (20.0 ppm after 24h) compared with solutions of clinically used p-boronophenylalanine (BPA) 5 (3.1 ppm after 24h). Carboranyl maltoside 3 was more effective than boron-10 enriched 5 in killing C-6 rat glioma cells by incubating the cells with the compound and subsequent treatment with thermal neutrons. 3 was also administrated iv, in concentrations of 25 mg boron/kg body weight to rats bearing brain tumors. After a period of 4h after administration the concentration of boron in the tumor tissue was 3.0 ppm.
Peptidyl boronic acids that are close structural analogues of good substrates have been prepared and evaluated as potential transition state analogue inhibitors of the representative cysteine protease, papain. However, no inhibition could be detected at concentrations up to 10 mM. The reasons for the lack of inhibition were sought from molecular modeling. Molecular mechanics and semi-empirical quantum mechanics calculations indicated that the absence of inhibition was due to boronic acid-cysteine protease tetrahedral complexes being 0.79 kcal mol-1 less stable than their preceding noncovalent EI-complexes. In contrast, an analogous boronic acid-serine protease tetrahedral complex was calculated to be 2.74 kcal mol-1 more stable than its precursor Michaelis EI-complex. It thus appears that boronic acids are ineffective inhibitors of cysteine proteases due to the thermodynamic favoring of a weak EI-complex preceding tetrahedral intermediate formation, and that any oxyanion hole stabilization of the subsequent tetrahedral intermediate cannot overcome this energy handicap.
We have developed a safe, simple, and efficient method for boron determination by means of direct-current plasma atomic emission spectroscopy. Tissues were solubilized by using concentrated sulfuric acid and 70% hydrogen peroxide to digest the samples without the need of high temperatures and pressures. Boron cluster compounds could be measured with sensitivity, precision, and accuracy similar to those of boric acid standards. Results obtained with [(C2H5)3NH]2B12H12, Cs2B12H11SH.H2O, and C15H32B10O6 show that this analytical method is applicable to a variety of compounds with different chemical structures. A sensitivity of 0.1 ppm has been obtained with known standards alone and in a variety of tissue matrices including tumor, blood, liver, skin, and cell suspensions. The measurement of total boron by direct-current plasma atomic emission spectroscopy (DCP-AES) has been achieved with as little as 50 mg of tissue or as few as 5 x 10(7) cells. The procedure is applicable to the analysis of boron in the ppm range with a high degree of precision and accuracy.
The gene encoding EGFR often is amplified in human gliomas, and the receptor itself has been considered as a potential target for the specific delivery of therapeutic agents to brain tumors. The purpose of the present study was to investigate the use of the chimeric MoAb cetuximab (IMC-C225), which is directed against EGFR and EGFRvIII, as a boron delivery agent for neutron capture therapy (NCT) of brain tumors. As determined by 125I-cetuximab radioligand binding assays, F98 rat glioma cells, which had been transfected with the gene encoding EGFR (F98EGFR), expressed 1.60 +/- 0.13 x 10(5) receptor sites/cell with a Ka = 1.64 +/- 0.32 x 10(8) M-1). F98 cells transfected with the gene encoding a mutant form of EGFR, designated the F98EGFRvIII glioma, expressed 1.07 +/- 0.10 x 10(5) receptor sites/cell with a Ka = 2.18 +/- 0.54 x 10(9) M-1 compared to background levels expressed on F98 wild-type cells (F98WT). A heavily boronated, fifth generation polyamidoamine (PAMAM or "starburst") dendrimer, G5-B1100, was linked to oligosaccharide moieties, which were distant from antigen binding sites of cetuximab, by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and N-(k-maleimidoundecanoic acid) hydrazide (KMUH). The resulting bioconjugate, designated C225-G5-B1100, was separated from the unconjugated dendrimer using a Sephacryl S-300 column. On the basis of the relative concentration ratios of boron and protein, there were approximately 1100 boron atoms per molecule of cetuximab with only a slight reduction of Ka. The localization of C225-G5-B1100 or G5-B1100 in rats bearing intracerebral implants of either F98EGFR or F98WT gliomas was determined 24 h following direct intratumoral (i.t.) injection at which time 92.3 +/- 23.3 micrograms B/g tumor was localized in F98EGFR gliomas versus 36.5 +/- 18.8 micrograms B/g tumor in F98WT gliomas and 13.4 +/- 6.1 micrograms in normal brain. In contrast, only 6.7 +/- 3.6 micrograms B/g tumor of G5-B1100 was localized in F98EGFR gliomas following i.t. injection, thereby demonstrating specific molecular targeting of EGFR. Based on these data, BNCT studies will be initiated in F98EGFR glioma bearing rats to evaluate C225-G5-B1100 for the treatment of intracerebral brain tumors.
The development of bioelectronic enzyme applications requires the immobilization of active proteins onto solid or colloidal substrates such as gold. Coverage of the gold surface with alkanethiol self-assembled monolayers (SAMs) reduces nonspecific adsorption of proteins and also allows the incorporation onto the surface of ligands with affinity for complementary binding sites on native proteins. We present in this work a strategy for the covalent immobilization of glycosylated proteins previously adsorbed through weak, reversible interactions, on tailored SAMs. Boronic acids, which form cyclic esters with saccharides, are incorporated into SAMs to weakly adsorb the glycoprotein onto the electrode surface through their carbohydrate moiety. To prevent protein release from the electrode surface, we combine the affinity motif of boronates with the reactivity of epoxy groups to covalently link the protein to heterofunctional boronate-epoxy SAMs. The principle underlying our strategy is the increased immobilization rate achieved by the weak interaction-induced proximity effect between slow reacting oxyrane groups in the SAM and nucleophilic residues from adsorbed proteins, which allows the formation of very stable covalent bonds. This approach is exemplified by the use of phenylboronates-oxyrane mixed monolayers as a reactive support and redox-enzyme horseradish peroxidase as glycoprotein for the preparation of peroxidase electrodes. Quartz crystal microbalance, atomic force microscopy, and electrochemical measurements are used to characterize these enzymatic electrodes. These epoxy-boronate functional monolayers are versatile, stable interfaces, ready to incorporate glycoproteins by incubation under mild conditions.
A novel approach for the potentiometric detection of saccharides using poly(aniline boronic acid) is presented. A model is described in which the electrochemical potential is sensitive to the change in the pK(a) of the conducting polymer as a result of boronic acid-diol complexation. In this system, boronic acid complexation is the mode of transduction and it is manifested as changes in the electrochemical potential of the polymer with remarkable selectivity. Characteristics of both transient and steady-state response associated with the complexation are discussed. The presence of Nafion and fluoride during the electrochemical polymerization of 3-aminophenylboronic acid are shown to impact the sensitivity and the stability of the electrode response. The sensor sensitivity is improved significantly by increasing the concentration of sodium fluoride during the polymerization. Finally, the nature of the selectivity of the boronic acid-diol reaction under these conditions is explored by using molecular orbital calculations.
The first example of a working model of the photosynthetic antenna-reaction center complex, constructed via self-assembled supramolecular methodology, is reported. For this, a supramolecular triad is assembled by axially coordinating imidazole-appended fulleropyrrolidine to the zinc center of a covalently linked zinc porphyrin-boron dipyrrin dyad. Selective excitation of the boron dipyrrin moiety in the boron dipyrrin-zinc porphyrin dyad resulted in efficient energy transfer (k(ENT)(singlet) = 9.2 x 10(9) s(-)(1); Phi(ENT)(singlet) = 0.83) creating singlet excited zinc porphyrin. Upon forming the supramolecular triad, the excited zinc porphyrin resulted in efficient electron transfer to the coordinated fullerenes, resulting in a charge-separated state (k(cs)(singlet) = 4.7 x 10(9) s(-)(1); Phi(CS)(singlet) = 0.9). The observed energy transfer followed by electron transfer in the present supramolecular triad mimics the events of natural photosynthesis. Here, the boron dipyrrin acts as antenna chlorophyll that absorbs light energy and transports spatially to the photosynthetic reaction center, while the electron transfer from the excited zinc porphyrin to fullerene mimics the primary events of the reaction center where conversion of the electronic excitation energy to chemical energy in the form of charge separation takes place. The important feature of the present model system is its relative "simplicity" because of the utilized supramolecular approach to mimic rather complex "combined antenna-reaction center" events of photosynthesis.