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PubMed2007

2-Aminoethoxydiphenyl borate as a common activator of TRPV1, TRPV2, and TRPV3 channels.

2-Aminoethoxydiphenyl borate (2APB) had been depicted as a universal blocker of transient receptor potential (TRP) channels. While evidence has accumulated showing that some TRP channels are indeed inhibited by 2APB, especially in heterologous expression systems, there are other TRP channels that are unaffected or affected very little by this compound. More interestingly, the thermosensitive TRPV1, TRPV2, and TRPV3 channels are activated by 2APB. This has been demonstrated both in heterologous systems and in native tissues that express these channels. A number of 2APB analogs have been examined for their effects on native store-operated channels and heterologously expressed TRPV3. These studies revealed a complex mechanism of action for 2APB and its analogs on ion channels. In this review, we have summarized the current results on 2APB-induced activation of TRPV1-3 and discussed the potential mechanisms by which 2APB may regulate TRP channels.

Animals↗

PubMedDate not supplied

Use of fluorescence polarization detection for the measurement of fluopeptidetm binding to G protein-coupled receptors.

G protein-coupled receptors (GPCRs) represent the single largest molecular target of therapeutic drugs currently on the market, and are also the most common target in high throughput screening assays designed to identify potential new drug candidates. A large percentage of these assays are now formatted as radioligand binding assays. Fluorescence polarization ligand binding assays can offer a non-rad alternative to radioligand binding assays. In addition, fluorescence polarization assays are a homogenous format that is easy to automate for high throughput screening. We have developed a series of peptide ligands labeled with the fluorescent dye BODIPY TMR whose binding to GPCRs can be detected using fluorescence polarization methodology. BODIPY TMR has advantages over the more commonly used fluorescein dye in high throughput screening (HTS) assays due to the fact that its excitation and emission spectra are red-shifted approximately 50 nm relative to fluorescein. Assays based on BODIPY TMR ligands are therefore less susceptible to interference from tissue auto-fluorescence in the assay matrix, or the effects of colored or fluorescent compounds in the screening libraries. A series of BODIPY TMR labeled peptides have been prepared that bind to a range of GPCRs including melanin concentrating hormone, bradykinin, and melanocortin receptors. Conditions have been optimized in order to utilize a comparable amount of receptor membrane preparation as is used in a radioligand binding assay. The assays are formatted in 384-well microplates with a standard volume of 40 microL. We have compared the assays across the different fluorescence polarization (FP) readers available to determine the parameters for each instrument necessary to achieve the required precision.

Binding, Competitive↗

PubMed2004

Spontaneous nucleotide exchange in low molecular weight GTPases by fluorescently labeled gamma-phosphate-linked GTP analogs.

Regulated guanosine nucleotide exchange and hydrolysis constitute the fundamental activities of low molecular weight GTPases. We show that three guanosine 5'-triphosphate analogs with BODIPY fluorophores coupled via the gamma phosphate bind to the GTPases Cdc42, Rac1, RhoA, and Ras and displace guanosine 5'-diphosphate with high intrinsic exchange rates in the presence of Mg(2+) ions, thereby acting as synthetic, low molecular weight guanine nucleotide exchange factors. The accompanying large fluorescence enhancements (as high as 12-fold), caused by a reduction in guanine quenching of the environmentally sensitive BODIPY dye fluorescence on protein binding, allow for real-time monitoring of this spontaneous nucleotide exchange in the visible spectrum with high signal-to-noise ratios. Binding affinities increased with longer aliphatic linkers connecting the nucleotide and BODIPY fluorophore and were in the 10-100 nM range. Steady-state and time-resolved fluorescence spectroscopy showed an inverse relationship between linker length and fluorescence enhancement factors and differences in protein-bound fluorophore mobilities, providing optimization criteria for future applications of such compounds as efficient elicitors and reporters of nucleotide exchange. EDTA markedly enhanced nucleotide exchange, enabling rapid loading of GTPases with these probes. Differences in active site geometries, in the absence of Mg(2+), caused qualitatively different reporting of the bound state by the different analogs. The BODIPY analogs also prevented the interaction of Cdc42 with p21 activated kinase. Together, these results validate the use of these analogs as valuable tools for studying GTPase functions and for developing potent synthetic nucleotide exchange factors for this important class of signaling molecules.

Boron Compounds↗

PubMed1998

Mechanism of action of diazaborines.

The diazaborine family of compounds have antibacterial properties against a range of gram-negative bacteria. Initially, this was thought to be due to the prevention of lipopolysaccharide synthesis. More recently, the molecular target of diazaborines has been identified as the NAD(P)H-dependent enoyl acyl carrier protein reductase (ENR), which catalyses the last reductive step of fatty acid synthase. ENR from Mycobacterium tuberculosis is the target for the front-line antituberculosis drug isoniazid. The emergence of isoniazid resistance strains of M. tuberculosis, a chronic infectious disease that already kills more people than any other infection, is currently causing great concern over the prospects for its future treatment, and it has reawakened interest in the mechanism of diazaborine action. Diazaborines only inhibit ENR in the presence of the nucleotide cofactor, and this has been explained through the analysis of the x-ray crystallographic structures of a number of Escherichia coli ENR-NAD+-diazaborine complexes that showed the formation of a covalent bond between the boron atom in the diazaborines and the 2'-hydroxyl of the nicotinamide ribose moiety that generates a noncovalently bound bisubstrate analogue. The similarities in catalytic chemistry and in the conformation of the nucleotide cofactor across the wider family of NAD(P)-dependent oxidoreductases suggest that there are generic opportunities to mimic the interactions seen here in the rational design of bisubstrate analogue inhibitors for other NAD(P)H-dependent oxidoreductases.

Anti-Bacterial Agents↗

PubMed1989

The identification of 5,6-dihydrouridine in normal human urine by combined gas chromatography/mass spectrometry.

The identification of 5,6-dihydrouridine in normal human urine is reported. Partial purification and isolation of the compound by boronate gel affinity chromatography and reversed-phase high-performance liquid chromatography preceded its characterization as a trimethylsilyl derivative by combined gas chromatography/mass spectrometry. Structure proof is based upon a comparison of mass spectral and chromatographic features of the urinary component to that of an authentic reference sample. Additional data derived from high resolution mass measurements and deuterium isotope-labeling experiments provide confirmation of fragment ion structure. The poor detectability inherent in the HPLC/uv analysis of nucleosides is also discussed.

Chromatography, Affinity↗

PubMed2002

Time course and magnitude of the calcium release induced by bright light in salamander rods.

Changes in fluorescence were measured with an argon ion laser from the outer segments of isolated salamander rods containing the Ca(2+)-sensitive fluorescent dye fluo-5F. When the outer segments were exposed to a 0Ca(2+)/0Na(+) solution designed to minimise surface membrane Ca(2+) fluxes, exposure to intense light from the laser evoked a slow increase in fluorescence, reflecting a light-induced rise in outer segment [Ca(2+)](i). The time course of this slow fluorescence rise could be fitted with the sum of two asymptotic exponential functions of approximately equal amplitude, having time constants of approximately 200 ms and 5.7 s. When rods were exposed to saturating background light to reduce outer segment [Ca(2+)](i) before laser illumination, the relative amplitude of the two exponentials was altered so as to reduce the contribution from the one with the shorter time constant. Examination of the initial time course of fluorescence when recording at high temporal resolution revealed a further rapid rise with a time constant of 1-2 ms, which could be observed even from rods in Ringer solution. This initial rapid rise could be abolished by pre-exposing the rod to bleaching illumination, whether the bleach was given in Ringer solution or in 0Ca(2+)/0Na(+) solution. It would therefore appear that the rapid rise in fluorescence is generated in some way by the bleaching of the photopigment. Unlike the slower components of fluorescence increase, the rapid initial rise was virtually unaffected in waveform or amplitude when rods were pre-exposed in Ringer solution to light which was bright enough to suppress completely the circulating current but which bleached a negligible fraction of the photopigment. Furthermore, pre-incubation with the AM ester of the Ca(2+) chelator BAPTA, although completely abolishing the slower components of fluorescence increase, had virtually no effect on the rapid rise. These results indicate that the rapid component, though triggered by rhodopsin bleaching, does not reflect an increase in outer segment [Ca(2+)](i). Neither the rapid nor the slower components of fluorescence increase were affected by exposure of the outer segment to 10 microM of the membrane-permeant compound N,N,N',N'-tetrakis(2-pyridyl-methyl)ethylenediamine (TPEN), which chelates heavy metals such as Zn(2+), or 100 microM 2-aminoethoxydiphenylborate (2-APB), a membrane-permeant blocker of IP(3) receptors. These results appear to exclude a role for changes in heavy metal concentration or Ca(2+) release via IP(3) receptors in the light-induced increases in dye fluorescence. Estimates of absolute Ca(2+) concentration and of rod buffering capacity suggest that the slower components of fluorescence increase represent the release of around 10-50 micromoles Ca(2+) per litre cytoplasmic volume from bound or sequestered stores after bleaching.

Ambystoma↗

PubMed2005

Solution conformation and dynamics of the ion pairs originating from the reaction of B(C6F5)3 with bisindenyl dimethyl zirconium complexes.

The two ion pairs [(4,7-Me(2)indenyl)(2)ZrMe](+)[MeB(C(6)F(5))(3)](-) (1 b) and [(indenyl)(2)ZrMe](+) [MeB(C(6)F(5))(3)](-) (2 b) have been generated in situ by reaction of stoichiometric B(C(6)F(5))(3) with the corresponding dimethyl zirconocenes. It has been shown that molecular mechanics computations, guided by experimental (1)H/(1)H NOE correlations, can provide information on the conformers present in solution. The dynamics of the ion pairs has also been investigated, showing the occurrence of both the processes previously characterized for this class of compounds, namely the B(C(6)F(5))(3) migration between the two methyl groups and dissociation-recombination of the whole [MeB(C(6)F(5))(3)](-) anion, the latter process being much faster than the first one (about three order of magnitude). Moreover, it has been shown that in certain conditions intermolecular processes can occur, which mimic the above-mentioned dissociative exchanges. In particular, the presence of species containing loosely bound [MeB(C(6)F(5))(3)](-) anion fastens the exchange of this anion, while the presence of free B(C(6)F(5))(3) accelerates its exchange between the two methyl sites.

Algorithms↗

PubMed2002

Xenobiotic efflux pumps in isolated fish brain capillaries.

To identify specific transporters that drive xenobiotics from the central nervous system to blood, the accumulation of fluorescent drugs was studied in isolated capillaries from killifish and dogfish shark brain using confocal microscopy and quantitative image analysis. In killifish brain capillaries, luminal accumulation of fluorescent derivatives of cyclosporin A and verapamil was concentrative, specific, and energy dependent (inhibition by KCN). Transport was reduced by PSC-833, but not by leukotriene C4, indicating the involvement of P-glycoprotein. The ability of capillaries to transport the cyclosporin A derivative was unchanged over 20 h, demonstrating the long-term viability of the preparation. Luminal accumulation of the fluorescent organic anions sulforhodamine 101 and fluorescein-methotrexate was also concentrative, specific, and energy dependent. Transport of these compounds was reduced by leukotriene C4, but not by PSC-833, indicating the involvement of a multidrug resistance-associated protein (Mrp). Similar results were obtained for isolated capillaries from dogfish shark. Immunostaining localized P-glycoprotein and Mrp2 to the luminal surface of the killifish brain capillary endothelium. These findings validate a new and long-lived comparative model for studying drug transport across the blood-brain barrier and, as in mammals, implicate P-glycoprotein and Mrp2 in transport from the central nervous system to blood in fish.

4-Chloro-7-nitrobenzofurazan↗

PubMed2001

A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase.

Enoyl acyl carrier protein (ACP) reductase catalyses the last reductive step of fatty acid biosynthesis, reducing the enoyl group of a growing fatty acid chain attached to ACP to its acyl product using NAD(P)H as the cofactor. This enzyme is the target for the diazaborine class of antibacterial agents, the biocide triclosan, and one of the targets for the front-line anti-tuberculosis drug isoniazid. The structures of complexes of Escherichia coli enoyl-ACP reductase (ENR) from crystals grown in the presence of NAD+ and a family of diazaborine compounds have been determined. Analysis of the structures has revealed that a mobile loop in the structure of the binary complex with NAD+ becomes ordered on binding diazaborine/NAD+ but displays a different conformation in the two subunits of the asymmetric unit. The work presented here reveals how, for one of the ordered conformations adopted by the mobile loop, the mode of diazaborine binding correlates well with the activity profiles of the diazaborine family. Additionally, diazaborine binding provides insights into the pocket on the enzyme surface occupied by the growing fatty acid chain.

Binding Sites↗

PubMed1995

Synthesis and biological properties of water-soluble p-boronophenylalanine derivatives. Relationship between water solubility, cytotoxicity, and cellular uptake.

Water-soluble p-boronophenylalanine (BPA) derivatives having cascade polyols, the monohydroxy derivative BPA(OH) (4), the dihydroxy analogue BPA(OH)2 (5), and the tetrahydroxy analogue BPA(OH)4 (6), were synthesized in order to elucidate a relationship between the molecular structures and the cellular uptake. Biological properties of these compounds in addition to BPA (1) itself were investigated. Water solubility increased in the order of BPA < BPA(OH) < or = BPA(OH)2 > BPA(OH)4. Cytotoxicity to B-16 melanoma and TIG hybrobrast cells decreased in the order of BPA >> BPA(OH) > or = BPA(OH)2 > BPA(OH)4. The cellular uptake by both B-16 and TIG cells decreased in the order of BPA > BPA(OH) > or = BPA(OH)2 > BPA(OH)4, whereas the uptake ratio of B-16/TIG increased in the order of BPA < BPA(OH) < or = BPA(OH)2 < BPA(OH)4. The latter ratio indicates the selectivity on the uptake by a cancer to normal cell.

Antineoplastic Agents↗

PubMed1983

Tetraphenylboron causes Ca2+ release in isolated sarcoplasmic reticulum and in skinned muscle fibers.

The lipophilic anion tetraphenylboron (TPB-) but not the lipophilic cation tetraphenylarsonium (TPA+) inhibited ATP-dependent Ca2+ accumulation by isolated sarcoplasmic reticulum. TPB- did not inhibit ATP hydrolysis but did induce Ca2+ release from preloaded vesicles. It did not appear to disrupt lipid bilayers or to act as a Ca2+ ionophore since it had no effect on the Ca2+ content of phospholipid vesicles. TPB- also induced Ca2+ release from sarcoplasmic reticulum in chemically skinned muscle fibers causing tension development. In contrast to other Ca2+-releasing agents such as caffeine, proton ionophores, or quercetin, the rise to peak tension was slow and tension was sustained, suggesting that Ca2+ release channels, once opened by TPB-, were held open as long as the compound was present in the membrane. Ca2+ uptake was re-established upon removal of TPB- or addition of TPA+. TPB- or TPA+ would probably distribute within the membrane, altering surface charges on both sides of the membrane. The fact that only a negatively charged ion brought about opening of Ca2+ release channels suggests that specific surface charges control Ca2+ release channels in sarcoplasmic reticulum. Although we have not been able to prove that TPB- acts exclusively on physiologically relevant Ca2+ release channels, we have shown that TPB- does not release Ca2+ from proteoliposomes reconstituted with the Ca2+ + Mg2+ ATPase. Thus TPB- does not induce Ca2+ release through channels formed by the ATPase molecule.

Animals↗

PubMed2002

Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2.

A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.

Boron Compounds↗

PubMed1991

The cytotoxicity of amine-cyanoboranes, amine-cyanoalkylboranes and aminomethyl-phosphonate cyanoborane adducts against the growth of murine and human tissue culture cells.

The amine-cyanoboranes, the amine-cyanoalkylboranes and the aminomethyl-phosphonate-N-cyanoborane adducts proved to be active antineoplastic agents. These compounds were more effective against single cell cultured cell growth rather than solid tumors. The following amine-cyanoboranes, (CH3)2(C18H37)NBH2CN (5), (CH3)2NHBH[CH(CH3)2]CN (7) and (CH3)3NB(CN)2.CH3 (10), were the most active in vivo and in vitro. A related phosphine-cyanoborane was also very active in both in vivo and in vitro model screens. Of the amino-methyl-phosphonate-N-cyanoborane adducts, (CH3O)2.P(O)CH2N(C2H5)2BH2CN (13) proved to be the most active. The amine-cyanoalkylboranes had the poorest in vivo activity; the in vitro cytotoxicity, however, was similar to that of other cyanoboranes.

Amines↗

PubMed2005

Compound-specific delta13C analysis of individual amino sugars--a tool to quantify timing and amount of soil microbial residue stabilization.

There is strong scientific evidence that microbial residues such as amino sugars may be stabilized in soil. However, up to now, no investigation has been carried out to quantify both the amount and timing of such stabilization. This is primarily due to methodological constraints, because it is not possible to differentiate between stabilized (old) and recently produced (new) amino sugars when these biomarkers are conventionally analyzed, e.g. by means of gas chromatography and flame ionization detection. Therefore, the aim of the present study was to test whether compound-specific isotope analysis (delta13C) of amino sugars extracted from soil could be used to differentiate between old and new microbial residues. For this aim a method for the delta13C analysis of individual amino sugars was developed and optimized. First results of delta13C values of glucosamine, galactosamine, mannosamine, and muramic acid in soil samples from two different ecological studies are presented, clearly indicating that discrimination between soil inherent and newly formed amino sugars is possible in stable isotope labeling experiments. Our results further showed that, in the short term (within 1 month), only few amino sugars were built, thus making highly 13C-enriched substrates necessary for the quantification of new amino sugar production and for the determination of amino sugar turnover rates.

Amino Sugars↗

PubMed2005

BODIPY-based hydroxyaryl derivatives as fluorescent pH probes.

[structures: see text] Seven new 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes with phenolic or naphtholic subunits on position 8 and with substituents having different electron driving forces on positions 3 and 5 were synthesized. Their absorption and steady-state fluorescence properties were investigated as a function of solvent. The novel compounds, with the exception of 4,4-difluoro-8-(4-hydroxyphenyl)-3,5-bis-(4-methoxyphenyl)-4-bora-3a,4a-diaza-s-indacene, are characterized by absorption maxima in the range 493-515 nm and small (400-600 cm(-1)) Stokes shifts. The exceptional dye has absorption maxima in the 570-580 nm region and fluorescence emission maxima around 610-620 nm, depending on the solvent. In aqueous solution, the dyes show a large fluorescent enhancement upon increasing the acidity of the solution. They can be used in aqueous solution as fluorescent pH probes excitable with visible light, with pKa values ranging from 7.5 to 9.3, depending on the substitution pattern on positions 3, 5, and 8.

Boron Compounds↗

PubMed2006

A novel layer-by-layer approach for the fabrication of conducting polymer/RNA multilayer films for controlled release.

Poly(anilineboronic acid) (PABA)/ribonucleic acid (RNA) multilayer films were prepared under neutral condition using a layer-by-layer deposition of PABA and RNA. RNA was used both as a polyelectrolyte for multilayer formation as well as dopant for PABA. Photoelastic modulated infrared reflection absorption spectroscopy measurements suggest that PABA interacts covalently with RNA through the formation of a boronate ester, a boron-nitrogen dative bond, as well as electrostatic interactions of anionic phosphates with cationic amines. The deposition procedure was monitored with UV-vis absorption spectroscopy, showing a linear dependence of absorbance with the number of PABA/RNA bilayers deposited. The multilayer films were further characterized using X-ray photoelectron spectroscopy and ellipsometry, which yielded a PABA/RNA bilayer thickness of approximately 10 nm. The PABA/RNA multilayer films are redox-active at neutral pH, consistent with the formation of a self-doped polymer. Electrochemical control of PABA under these conditions allows potential-induced controlled release of RNA from a multilayer at neutral pH, suggesting that this may serve as a novel method for controlled release of RNA under physiological conditions.

Aniline Compounds↗

PubMed1993

Evaluation of two novel biochemicals on plasma and egg yolk lipid composition and laying hen performance.

PD132301-2, an inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT; EC 2.3.1.26), and 1-stearylboronic acid (SBA), a fatty acid analogue, were orally administered to White Leghorn hens in separate experiments to evaluate their effects on layer performance and plasma and egg yolk lipids. Five 60-wk-old hens each were fed either a corn-soybean meal basal layer ration, or the basal diet supplemented with .0121, .0363, or .1089% PD132301-2. In a second experiment, 12 37-wk-old hens each were fed either a basal layer ration, or the basal diet supplemented with .20 or .40% SBA. The duration of the experiments were 21 and 16 days, respectively. Neither compound significantly affected hen-day production, egg weight, yolk weight, BW gain, feed consumption, feed efficiency, plasma total cholesterol and triglyceride concentrations, or egg yolk cholesterol content. PD132301-2 had no effect on yolk fatty acid profiles, and C22:6n3 was the only fatty acid altered by SBA. Although 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have been successful in reducing egg cholesterol, ACAT inhibitors and fatty acid analogues apparently hold little promise in this regard. The results of the present work also support the concept that, in order to pharmacologically alter the cholesterol content of eggs, direct inhibition of key enzymes in the cholesterol biosynthetic pathway is necessary.

Administration, Oral↗

PubMed2006

Determination of haloperidol and reduced haloperidol in human serum by liquid chromatography after fluorescence labeling based on the Suzuki coupling reaction.

A simultaneous method for the determination of haloperidol (HP) and its metabolite, reduced haloperidol (RHP), in human serum was developed by means of high-performance liquid chromatography (HPLC) with fluorescence detection. Suzuki coupling reaction with a fluorescent arylboronic acid, 4-(4,5-diphenyl-1H-imidazol-2-yl)phenylboronic acid (DPA), was employed to convert HP and RHP into highly fluorescent compounds. HP and RHP were extracted from human serum by liquid-liquid extraction with a mixture of n-hexane and isoamyl alcohol (99:1, v/v) and subsequently labeled by reaction with DPA. Separation of DPA derivatives of HP and RHP was performed on a silica column with a mixture of acetonitrile and H(2)O (90:10, v/v) containing triethylamine and acetic acid as a mobile phase. The proposed method allowed sensitive detection of HP and RHP in human serum with a detection limit (at a signal to noise ratio of 3) of 0.22 and 0.20 ng/mL, respectively. The applicability of the method for therapeutic drug monitoring (TDM) was demonstrated by analyzing human serum samples from schizophrenic patients receiving HP.

Boron Compounds↗