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PubMedDate not supplied

Blood boron concentrations in pregnant rats fed boric acid throughout gestation.

Timed-mated Sprague-Dawley rats (28 to 32/group) were exposed to boric acid (BA) in the diet from Gestational Day (GD) 0 to 20. Dietary concentrations of added BA (0%, 0.025%, 0.050%, 0.075%, 0.100%, or 0.200%) yielded average daily intakes equivalent to 0, 3, 6, 10, 13, or 25 mg boron/kg body weight/d. Dams and their fetuses were evaluated for evidence of maternal or developmental toxicity, as reported previously. At termination on GD 20, maternal whole blood was collected in heparinized Vacutainer tubes, stored frozen (-20 degrees C), and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry. Increasing dietary concentrations of BA were positively associated with whole blood boron concentrations in confirmed pregnant rats, specifically 0.229 +/- 0.143, 0.564 +/- 0.211, 0.975 +/- 0.261, 1.27 +/- 0.298, 1.53 +/- 0.546, or 2.82 +/- 0.987 micrograms boron/g whole blood (mean +/- SD) for the control through high-dose groups. Maternal blood boron concentrations were positively correlated with indices of maternal dietary intake of boron and with embryo/fetal toxicity observed at 0.100% and 0.200% BA in the diet reported previously. Thus, blood boron concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 micrograms boron/g were associated with the no-observed-adverse-effect level (10 mg boron/kg/d) and lowest-observed-adverse-effect level (13 mg boron/kg/d) for developmental toxicity reported previously.

Animals↗
PubMed2000

Effects of boron derivatives on extracellular matrix formation.

Boric acid solution (3%) dramatically improves wound healing through action on the extracellular matrix, a finding that has been obtained in vitro. Consequently, investigations are presently underway to produce boronated compounds having a therapeutical effectiveness similar to that of boric acid. On the basis of experimental results obtained with boric acid, we examined the effects of boron derivatives on extracellular matrix formation and degradation and analyzed their potential toxicity by using two biological models (chick embryo cartilage and human fibroblasts). The four boron derivatives tested in this study (triethanolamine borate; N-diethyl-phosphoramidate-propylboronique acid; 2,2 dimethylhexyl-1,3-propanediol-aminopropylboronate and 1,2 propanediol-aminopropylboronate) mimicked the effects of boric acid. They induced a decrease of intracellular concentrations in extracellular matrix macromolecules (proteoglycans, proteins)-associated with an increase of their release in culture medium and stimulated the activity of intra- and extracellular proteases. Similarly to boric acid, these actions occurred after exposure of the cells to concentrations of all boron derivatives without apparent toxic effects. The compounds were found to be more toxic than boric acid itself when concentrations were calculated according to their molecular weight. Nevertheless, these in vitro preliminary results demonstrate effects of boron derivatives that may be of therapeutic benefit in wound repair.

Animals↗
PubMedDate not supplied

Unilamellar liposomes with enhanced boron content.

A new type of boron-rich, DSPC-free, unilamellar liposomes was formed using the novel dual-chain, ionic, nido-carborane lipid, K[nido-7-(C16H33OCH2)2CHOCH2-7,8-C2B9H11] (DAC-16), and cholesterol for encapsulation of an aqueous buffer core. Since DSPC was not necessary for the formation of stable DAC-16 liposomes, the boron concentration of these vesicles was increased dramatically to approximately 8.8 wt % in the dry lipid; these liposomes had a high bilayer boron incorporation efficiency of 98%. DSPC-free liposomes exhibited a size distribution pattern of 40-60 nm, which was in the range normally associated with selective tumor uptake. This size distribution was maintained throughout storage at room temperature for several months. Additionally, optimized liposome formulations incorporating DAC-16, DSPC, and cholesterol were identified having stable size distribution patterns after storage for more than two months at a variety of temperatures. Although animal studies indicate that DAC-16 liposomes are toxic, this new ionic nido-carborane lipid allows the formation of liposomes of high boron content for in vitro applications that require the delivery of large amounts of boron.

Animals↗
PubMed1992

Identification of serine and histidine adducts in complexes of trypsin and trypsinogen with peptide and nonpeptide boronic acid inhibitors by 1H NMR spectroscopy.

We have previously shown, in 15N NMR studies of the enzyme's active site histidine residue, that boronic acid inhibitors can form two distinct types of complexes with alpha-lytic protease. Inhibitors that are structural analogs of good alpha-lytic protease substrates form transition-state-like tetrahedral complexes with the active site serine whereas those that are not form complexes in which N epsilon 2 of the active site histidine is covalently bonded to the boron of the inhibitor. This study also demonstrated that the serine and histidine adduct complexes exhibit quite distinctive and characteristic low-field 1H NMR spectra [Bachovchin, W. W., Wong, W. Y. L., Farr-Jones, S., Shenvi, A. B., & Kettner, C. A. (1988) Biochemistry 27, 7689-7697]. Here we have used low-field 1H NMR diagnostically for a series of boronic acid inhibitor complexes of trypsin and trypsinogen. The results show that H-D-Val-Leu-boroArg and Ac-Gly-boroArg, analogs of good trypsin substrates, form transition-state-like serine adducts with trypsin, whereas the nonsubstrate analog inhibitors boric acid, methane boronic acid, butane boronic acid, and triethanolamine borate all form histidine adducts, thereby paralleling the previous results obtained with alpha-lytic protease. However, with trypsinogen, Ac-Gly-boroArg forms predominantly a histidine adduct while H-D-Val-Leu-boroArg forms both histidine and serine adducts, with the histidine adduct predominating below pH 8.0 and the serine adduct predominating above pH 8.0.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗
PubMed1998

Structure-based enhancement of boronic acid-based inhibitors of AmpC beta-lactamase.

The expression of beta-lactamases is the most common form of bacterial resistance to beta-lactam antibiotics. To combat these enzymes, agents that inhibit (e.g. clavulanic acid) or evade (e.g. aztreonam) beta-lactamases have been developed. Both the beta-lactamase inhibitors and the beta-lactamase-resistant antibiotics are themselves beta-lactams, and bacteria have responded to these compounds by expressing variant enzymes resistant to inhibition (e.g. IRT-3) or that inactivate the beta-lactamase-resistant antibiotic (e.g. TEM-10). Moreover, these compounds have increased the frequency of bacteria with intrinsically resistant beta-lactamases (e.g. AmpC). In an effort to identify non-beta-lactam-based beta-lactamase inhibitors, we used the crystallographic structure of the m-aminophenylboronic acid-Escherichia coli AmpC beta-lactamase complex to suggest modifications that might enhance the affinity of boronic acid-based inhibitors for class C beta-lactamases. Several types of compounds were modeled into the AmpC binding site, and a total of 37 boronic acids were ultimately tested for beta-lactamase inhibition. The most potent of these compounds, benzo[b]thiophene-2-boronic acid (36), has an affinity for E. coli AmpC of 27 nM. The wide range of functionality represented by these compounds allows for the steric and chemical "mapping" of the AmpC active site in the region of the catalytic Ser64 residue, which may be useful in subsequent inhibitor discovery efforts. Also, the new boronic acid-based inhibitors were found to potentiate the activity of beta-lactam antibiotics, such as amoxicillin and ceftazidime, against bacteria expressing class C beta-lactamases. This suggests that boronic acid-based compounds may serve as leads for the development of therapeutic agents for the treatment of beta-lactam-resistant infections.

Anti-Bacterial Agents↗
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↗
PubMed2004

Boron-complexation strategy for use with 1-acyldipyrromethanes.

1-Acyldipyrromethanes are important precursors in rational syntheses of diverse porphyrinic compounds. 1-Acyldipyrromethanes are difficult to purify, typically streaking upon chromatography and giving amorphous powders upon attempted crystallization. A solution to this problem has been achieved by reacting the 1-acyldipyrromethane with a dialkylboron triflate (e.g., Bu2B-OTf or 9-BBN-OTf) to give the corresponding B,B-dialkyl-B-(1-acyldipyrromethane)boron(III) complex. The reaction is selective for a 1-acyldipyrromethane in the presence of a dipyrromethane. The 1-acyldipyrromethane-boron complexes are stable to routine handling, are soluble in common organic solvents, are hydrophobic, crystallize readily, and chromatograph without streaking. The 1-acyldipyrromethane can be liberated in high yield from the boron complex upon treatment with 1-pentanol. Alternatively, the 1-acyldipyrromethane-boron complex can be used in the formation of a trans-A2B2-porphyrin. In summary, the boron-complexation strategy has broad scope and greatly facilitates the isolation of 1-acyldipyrromethanes.

Acylation↗
PubMed1994

Fourier transform infrared (FTIR) spectrometry for the assay of polyhedral boron compounds in plasma and pharmaceutical formulations.

The determination of polyhedral boron compounds such as sodium borocaptate directly in blood plasma is described using FTIR with computed nonlinear background subtraction of the water absorption band. The procedure can be performed in less than 15 min to a sensitivity level of 5 ppm boron (as a signal/noise ratio of 2.5), which is satisfactory in the clinical application of such compounds in neutron capture therapy of cancer. For boron compounds with suitable organic solubility, extraction from plasma into carbon tetrachloride is described as an alternative approach not requiring computed subtraction and capable of achieving a sensitivity level of 1 ppm. Both the boron and the lipid content of liposome formulations containing the polyhedral boron compounds can be measured simultaneously by FTIR. After extraction into CHCl3:CH3OH (1:1) or dispersion in ethanol, the extracts are evaporated to dryness and redissolved in carbon tetrachloride for FTIR assay.

Boron Compounds↗
PubMed2003

Tumor-cell targeted epiderimal growth factor liposomes loaded with boronated acridine: uptake and processing.

PURPOSE: The aim of this work was to investigate the cellular binding and processing of polyethylene glycol-stabilized epidermal growth factor (EGF) liposomes. The liposomes were actively loaded with water-soluble boronated acridine (WSA), primarily developed for boron neutron capture therapy. METHODS: The uptake, internalization, and retention of EGF-liposome conjugates were studied in two cultured monolayer cell-lines, A-431 and U-343, with regard to the nuclide-label on the targeting agent, the carrier, and the load. The subcellular localization of WSA was studied using confocal microscopy. RESULTS: We found that the liposome complex was internalized after specific binding to the EGF receptor. After internalization in the tumor cells, WSA was distributed mainly in the cytoplasm and was shown to have long cellular retention, with 80% of the boron remaining after 48 h. CONCLUSIONS: The long retention of the compound and the cellular boron concentration reached makes these targeted liposomes interesting for further development toward boron neutron capture therapy.

Acridines↗
PubMed2006

Boronated protohaemins: synthesis and in vivo antitumour efficacy.

The conjugates of porphyrin macrocycles with boron-containing polyhedra are under investigation as agents for binary treatment strategies of cancer. Aiming at the design of photoactive compounds with low-to-zero dark toxicity, we synthesized a series of carboranyl and monocarbon-carboranyl derivatives of protohaemin IX using the activation of porphyrin carboxylic groups with di-tert-butyl pyrocarbonate or pivaloyl chloride. The water-soluble 1,3,5,8-tetramethyl-2,4-divinyl-6(7)-[2'-(closo-monocarbon-carborane-1''-yl)methoxycarbonylethyl]-7(6)-(2'-carboxyethyl)porphyrin Fe(III) (compound 9) exerted no discernible cytotoxicity for cultured mammalian cells, nor did it cause general toxicity in rats. Importantly, 9 demonstrated dose-dependent activity as a phototoxin in photodynamic therapy of M-1 sarcoma-bearing rats. In animals injected with 20 mg kg(-1) of 9, the tumours shrank by day 3 after one single irradiation of the tumour with red laser light. Between 7 and 14 days post-irradiation, 88.9% of rats were tumour-free; no recurrence of the disease was detectable within at least 90 days. Protohaemin IX alone was without effect, indicating that boronation is important for the phototoxic activity of 9. This is the first study that presents the synthesis and preclinical in vivo efficacy of boronated derivatives of protohaemin as phototoxins. The applicability in photodynamic treatment broadens the therapeutic potential of boronated porphyrins beyond their conventional role as radiosensitizers in boron neutron capture therapy.

Animals↗
PubMed1996

Effects of dietary boron supplementation on laying hens.

1. The effects of dietary boron on egg production and on the ultimate shear force, stress, and fracture energy of the tibia, femur, humerus, and radius from White Leghorn laying hens were investigated. 2. The shear force, stress, and fracture energy of the bones were not affected by increasing dietary concentrations of boron. 3. Egg production, food consumption and body weight were suppressed at a dietary boron concentration of 400 mg/kg. 4. Boron concentrations increased significantly in all tissue samples tested in birds given 400 mg/kg dietary boron.

Analysis of Variance↗
PubMed2003

The physiological effects of dietary boron.

Boron may be an essential nutrient for animals and humans. Dietary boron influences the activity of many metabolic enzymes, as well as the metabolism of steroid hormones and several micronutrients, including calcium, magnesium, and vitamin D. Boron supplementation in rats and chicks has been shown to increase bone strength. Boron may also play a role in improving arthritis, plasma lipid profiles, and brain function. Additional research is necessary to further clarify boron's influence in human and animal physiology, as well as determine a dietary requirement for humans.

Animals↗
PubMed1978

Calculated responses to a thermal neutron beam for hamster and HeLa cells containing boron-10 at different concentrations.

Hamster and HeLa cells containing boron-10 at different concentrations were irradiated by a thermal neutron beam from a reactor. The survival curves were calculated according to the Katz and Sharma theory of track structure for heavy charged particles. The thickness of cell specimens irradiated was taken to be 0.02 cm to enable the first collision dose to be used. The boron-10 concentrations were 0, 2,5, 10, 20, 40 and 60 microgram per g of tissue. For comparison with the experiments of Davis et al. the effect of fast neutorns was taken into account. Values for relative biological effectiveness (RBE) are given for different boron-10 concentrations and various surviving fractions. Isosurvival dose curves are defined and drawn which show the relation between neutron fluences and absorbed dose for different boron-10 concentrations. The RBE values increase with decreasing dose and change only slightly with increasing boron-10 concentration for an equal surviving fraction. Some differences were found between the calculated results for HeLa cells in the thin layer and the experimental data for the cells in a monolayer. The results of the calculations are discussed.

Animals↗
PubMed1998

Boron stimulates embryonic trout growth.

Boron is present in our soil, water and air. Cyanobacteria require it for nitrogen fixation, and vascular plants require it for the formation of cell walls and membranes. I report here how boron affects the growth of embryonic rainbow trout (Oncorhynchus mykiss). Fertilized ovum from the Mt. Whitney rainbow trout strain were incubated at (12.5 degreesC) in Type 1 ASTM ultrapure grade water supplemented with boric acid (99.5% purity) during the 1995 and 1997 spawning seasons. Boron concentrations of the incubation solutions were determined by direct measurement using the curcumin procedure or inductively coupled plasma-mass spectrometry. In the 1995 study boron ranged from 1 to 936 micromol/L. Ca, Na and Mg salts were included in the incubation solutions to approximate concentrations in natural water. In the 1997 study fertilized eggs were incubated in ultrapure water supplemented with boric acid alone over a range from 2.2 to 90.6 micromol/L. The 1995 study used 144 embryos per B concentration and the 1997 study used 96 embryos per B concentration. Growth and teratogenicity were evaluated at the eye, hatch and 2-wk posthatch developmental stages. Boron stimulated growth in a dose-dependent manner in both studies (P < 0.001), and exposure was associated with an increase in B body concentration (P < 0.05). No teratogenic or microbicidal effects were apparent. These results are consistent with those expected of an element essential for vertebrate development. J. Nutr. 2488-2493, 128: 1998

Animals↗
PubMed2005

Boron concentrations in milk from mothers of exclusively breast-fed healthy full-term infants are stable during the first four months of lactation.

Because boron is a bioactive element that satisfies several of the criteria for essentiality in humans, the aim of the present work was to determine the profile of boron metabolism in human milk during the first 4 mo of lactation. The concentration of boron and other minerals was determined in archived milk collected (1980-84) 1 time/mo for 4 mo from lactating mothers of full-term, exclusively breast-fed infants living in Houston, TX. A linear model (treating month as a continuous variable) indicated that B concentrations were stable (P = 0.14) between mo 1 [3.88 +/- 0.6 mumol (42 +/- 6.5 microg)/L milk] and 4 [3.24 +/- 0.6 micromol (35 +/- 6.5 microg)/L milk, mean +/- SEM]. Mg concentrations increased slightly over time (1.18 +/- 0.09 to 1.36 +/- 0.09 mmol/L, P < 0.0001), whereas Ca concentrations decreased slightly (7.01 +/- 0.29 to 6.68 +/- 0.29 mmol/L milk, P < 0.02) and Zn decreased substantially (0.04 +/- 0.004 to 0.02 +/- 0.004 mmol/L milk, P < 0.0001). Similarities in findings reported here and earlier (from samples collected in St. John's, Newfoundland) provide further evidence that boron may be metabolically regulated. Future investigations of boron regulatory mechanisms should focus on metabolism of bone as the major storage site of B and kidney excretion, the major excretory route for B.

Adult↗
PubMed2004

In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganese.

Matrix metalloproteinase (MMP)-2 and MMP-9 are involved in keratinocyte migration and granulation tissue remodeling during wound healing. Thermal water cures are sometimes proposed as complementary treatment for accelerating healing of wounds resulting from burns and/or surgery, but their mechanisms of action remain unknown. Some thermal waters are rich in trace elements such as boron and manganese. Interestingly, clinical studies have shown the beneficial effects of trace elements such as boron and manganese for human wound healing. To try to specify the role of trace elements in cutaneous healing, the present study investigated the effects of these trace elements on the production of MMP-2 and MMP-9 by normal human keratinocytes cultured in vitro. Immunohistochemistry and Western blot showed that intracellular MMP-9 expression in keratinocytes was induced when incubated for 6 h with boron at 10 micro g/ml or manganese at 0.2 micro g/ml. Moreover, gelatin zymography on keratinocyte supernatants showed an increase of gelatinase secretion after 24 h of incubation of keratinocytes with boron or manganese, regardless of concentration. Gelatinase secretion was not associated with keratinocyte proliferation induced by trace elements. Thus, our results suggest that boron and manganese could play a role in the clinical efficiency of thermal water on wound healing.

Blotting, Western↗
PubMedDate not supplied

Advances in analytical techniques for neutron capture therapy: thin layer chromatography matrix and track etch thin layer chromatography methods for boron-10 analysis.

A new track etch autoradiographic technique for quantitating boron-10 containing compounds used for neutron capture therapy is described. Instead of applying solutions of Cs2B12H11SH and its oxidation products directly to solid-state nuclear track detectors, diethylaminoethyl cellulose thin layer chromatography (TLC) plates are utilized as sample matrices. The plates are juxtaposed with Lexan polycarbonate detectors and irradiated in a beam of thermal neutrons. The detectors are then chemically etched, and the resultant tracks counted with an optoelectronic image analyzer. Sensitivity to boron-10 in solution reaches the 1 pg/microliter level, or 1 ppb. In heparinized blood samples, 100 pg boron-10/microliter are detected. This TLC matrix method has the advantage that sample plates can be reanalyzed under different reactor conditions to optimize detector response to the boron-10 carrier material. Track etch/TLC allows quantitation of the purity of boron neutron capture therapy compounds by utilizing the above method with TLC plates developed in solvent systems that resolve Cs2B12H11SH and its oxidative analogs. Detectors irradiated in juxtaposition to the thin layer chromatograms are chemically etched, and the tracks are counted in the sample lane from the origin of the plate to the solvent front. A graphic depiction of the number of tracks per field yields a quantitative analysis of compound purity.

Boron↗