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Halogenated boldine derivatives with enhanced monoamine receptor selectivity.

(S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. Initial halogenation occurs at C-3, followed (in the cases of chlorine and bromine) by the less reactive C-8, to afford 3-haloboldines- and 3,8-dihaloboldines (2-5). Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo derivative 6 was obtained. Radioligand binding studies of these products showed that halogenation of boldine at C-3 favors affinity for D(1)- (vs D(2)-) dopaminergic receptors, attaining a low nanomolar IC(50) value in the case of 3-iodoboldine (6).

Acetates↗

Molecular orbital-based quantitative structure-activity relationship for the cytochrome P450-catalyzed 4-hydroxylation of halogenated anilines.

The cytochrome P450 (P450) catalyzed 4-hydroxylation of halogenated anilines was investigated with special emphasis on possible relationships between kinetic parameters and physicochemical and electronic characteristics of the substrates. The most important observation of the present study was a correlation (r = 0.96) between the natural logarithm of the apparent maximum reaction rate kcats for 4-hydroxylation of the aniline substrates in a iodosobenzene-supported microsomal cytochrome P450-catalyzed reaction and the energy of the highest molecular orbital [E(HOMO)] of the anilines. This result is in accordance with a mechanism that proceeds by an initial electrophilic attack of the P450 (FeO)3+ intermediate on the frontier pi electrons of the aniline substrates. In the iodosobenzene-supported aniline 4-hydroxylation this electrophilic attack is the rate-limiting step. In the NADPH/oxygen-supported cytochrome P450-catalyzed 4-hydroxylation of the anilines a correlation of the natural logarithm of kcats with E(HOMO) was not observed and the kcats values were lower than observed in the iodosobenzene-supported reaction. From this result it is concluded that, although the NADPH/oxygen-supported microsomal 4-hydroxylation of the halogenated anilines proceeds by the same cytochrome P450 (FeO)3+ intermediate and, thus, by a similar electrophilic attack of the (FeO)3+ on the pi electrons of the substrate, this attack is no longer the rate-limiting step of the reaction. Additional results of the present study demonstrate that the apparent Michaelis constant Kms of the NADPH/oxygen-supported 4-hydroxylation of the anilines decreases with increasing hydrophobicity of the aniline derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophenols↗

Halogenated volatile anesthetics inhibit carbon monoxide-stimulated soluble guanylyl cyclase activity in rat brain.

BACKGROUND: Because of halogen contents, halogenated volatile anesthetics (HVA) have a similarity to nitric oxide (NO) in terms of great affinity for the ferrous ion. Interactions between HVA and NO at the ferrous ion of soluble guanylyl cyclase (sGC) have been reported in different tissues. Carbon monoxide (CO), a more stable gas than NO, activates sGC by the same mechanism as NO. This study was undertaken to examine the effect of HVA on CO-stimulated sGC activity in rat brain. METHODS: Sprague-Dawley rat brain was homogenized and ultracentrifuged. The resulting supernatant was used as sGC fraction. The fraction was incubated with CO and HVA, and the activity of sGC was determined by measuring cyclic guanosine monophosphate (cGMP) production using an enzyme immunoassay in aliquots of the supernatant. RESULTS: CO clearly increased cGMP production in a dose-dependent manner. Sevoflurane and isoflurane produced significant and dose-dependent inhibition of CO-stimulated sGC activity. There was no difference in the inhibitory effect between the two anesthetics. GTP dose-dependently increased CO-stimulated cGMP production. Both anesthetics decreased GTP production, but the inhibition by the anesthetics was not significant at higher GTP concentrations. CONCLUSIONS: These results suggest that HVA can compete with CO at the ferrous ion of sGC and inhibit the activity of this enzyme.

Anesthetics, Inhalation↗

Elution of TEGDMA and BisGMA from a resin and a resin composite cured with halogen or plasma light.

Plasma arc light units for curing resin composites have been introduced with the claim of relatively short curing times. The purpose of the present study was to measure and compare elution of monomers from an experimental BisGMA-TEGDMA resin and a commercial resin composite when cured with a halogen unit and when cured with a plasma arc unit. Specimens of the materials were immersed in methanol, and the amounts of monomers released with time were analyzed by HPLC. By use of Fick's laws of diffusion, the amount of eluted monomers from the specimen at infinity was estimated. The elution from resin specimens and from resin composite specimens cured with the plasma arc light unit was 7 and 4 times higher, respectively, compared to the elution from specimens cured with the halogen unit. It was concluded that the plasma arc light curing unit did not provide optimal cure when used as recommended by the manufacturer.

Analysis of Variance↗

Tropospheric lifetimes of halogenated anaesthetics.

Concern has been expressed over the use of the halogenated anaesthetics halothane (CF3CClBrH), enflurane (CF2HOCF2CFClH) and isoflurane (CF2HOCHClCF3) because of their potential for stratospheric ozone destruction. Halogenated species also contribute to global warming. The significance of the anaesthetics in stratospheric ozone loss or in 'greenhouse' heating depends on their atmospheric lifetimes. Because reaction with hydroxyl (OH) radicals is likely to be the main homogeneous sink for these species in the troposphere, we have measured absolute rates of reaction with OH. Comparison with a one-dimensional model indicates that the lifetimes of halothane, enflurane and isoflurane with respect to this reaction are 2, 6 and 5 years, respectively. Thus the small production of the anaesthetics is not offset by anomalously long atmospheric lifetimes to give a large atmospheric burden of the compounds. The anaesthetics will contribute at most a fraction of approximately 5 x 10(-4) to the total atmospheric content of chlorine-containing species.

Air Pollutants↗

A prospective randomized controlled study of phototherapy using blue and blue-green light-emitting devices, and conventional halogen-quartz phototherapy.

OBJECTIVE: To determine the efficacy of blue versus blue-green phototherapy using new light sources with narrow luminous spectra. The devices made of high-intensity gallium nitride light-emitting diodes (LEDs) were also compared to conventional halogen-quartz bulbs phototherapy. DESIGN: Prospective open randomized study. PARTICIPANTS: A total of 114 jaundiced, but otherwise healthy term infants who met the entry criteria for phototherapy set by the American Academy of Pediatrics' Practice Parameter. MAIN OUTCOME MEASURES: The duration of phototherapy and the rate of decrease in total serum bilirubin (TSB). RESULTS: The mean TSB concentrations at initiation and termination of treatment, as well as the duration of phototherapy and the rate of decrease in TSB, were not statistically different in newborns receiving blue LED, blue-green LED or conventional phototherapy. The average rate of decrease in TSB (slope), after adjustment by a linear regression analysis for confounding factors, was -3.61 micromol/hour (95% confidence limits -5.47, -1.75) in the 25 newborns receiving blue LED phototherapy compared with -2.57 micromol/hour (-4.32, -0.82) in the 22 newborns treated with blue-green LED phototherapy and -3.42 micromol/hour (-5.02, -1.81) in the 57 newborns who received conventional phototherapy. CONCLUSIONS: When using low light irradiance, there was no statistically significant difference in the effectiveness of phototherapy using blue-green LEDs, blue LEDs or conventional halogen-quartz bulbs.

Bilirubin↗

Patterns and levels of halogenated volatile compounds in Portuguese surface waters.

The present study focused on monitoring the concentration of 14 halogenated volatile organic compounds in surface waters, including sea, estuarine, river water and industrial effluents in order to determine the most ubiquitous compounds and their concentration levels, which were used to establish their geographical and temporal distribution. EPA Method 502, based on purge and trap techniques, was used. In this method volatile organic pollutants are extracted (purged) from the water sample by bubbling inert gas through the aqueous sample. Purged sample components are trapped in a cartridge containing the polymeric sorbent Tenax and, thereafter, the cartridge is heated and backflushed with helium to desorb the trapped sample components directly into a gas chromatograph with electron capture detector (GC-ECD). The linearity range of the method varied from 0.1 to 4 microg L(-1) with a limit of detection at the low microg L(-1) level. The present study consisted of a monthly monitoring of 46 points throughout Portugal, during 14 months. Chloroform was found in 50% of the samples analyzed, its presence being correlated to both agricultural and industrial activities. Other compounds detected were tetrachloroethylene, trichloroethylene, carbon tetrachloride and 1,2,4 trichlorobenzene, which were present in 10-20% of the samples at concentrations up to 18 microg L(-1). 1,1,2,2-Tetrachloroethane and its degradation product 1,1,2-trichloroethane were found in 5% of the samples, the levels of the latter being higher than those of the parent compound in most samples. Sporadic high concentrations of some volatile halogenated organic compounds were attributed to local uses as solvents.

Agriculture↗

The molecular structures of pentaborane(9) with halogen substituents in apical and basal positions, determined by electron diffraction and theoretical calculations.

The molecular structures of 1-bromo-pentaborane(9) and 2-bromo-pentaborane(9) in the gas phase have been determined by electron diffraction and ab initio and DFT computational methods. Computational methods have also been applied to the fluoro and chloro analogues, to 1,2-dibromo-pentaborane(9), and to the parent unsubstituted borane. The electronic effects of halogen substitution on the borane cage are remarkably small, particularly for chlorine and bromine substituents, and steric effects are also minimal, even in the compound with two bromine atoms. The largest effects are (a) lengthening of B((base))-B((apex)) bonds adjacent to the halogen in the 2-isomers, with an associated shortening of the opposite base-apex bond, (b) shortening of the B((base))-B((apex)) bond in the 1-fluoro compound, and (c) increase of the B((base))-B((apex))-F angle in 1-F-B(5)H(8), but a decrease in this angle in the 2-bromo compounds.

Journal Article↗

Oxidative addition of iodo-acetonitrile and of elemental halogens to [Pt3(mu-CO)3(PCy3)3].

The reaction of [Pt3(mu-CO)3(PCy3)3](1) with one mole-equivalent of iodo-acetonitrile was quantitative at -70 degrees C giving the oxidative addition product [Pt3(mu-CO)3(PCy3)3(I)(CH2CN)](2). Fragmentation of was observed in solution giving [Pt2I(CH2CN)(CO)2(PCy3)2](3) which is the major product at room temperature if the starting cluster/reactant ratio is equal to or less than 1 to 1.5. Dimer 3 decomposes slowly in solution giving [Pt2I2(CO)2(PCy3)2](4a) and succinonitrile. Monomer [PtI(CH2CN)(CO)(PCy3)] was the final product of the reaction when using excess of iodo-acetonitrile. The reactions of with one mole-equivalent of halogens X2 gave the new 44-electron clusters [Pt3X(micro-CO)2(micro-X)(PCy3)3](X = I2(7a) or Br2(7b)) by oxidative addition followed by substitution of CO by X-. Fragmentation of and took place in solution when using one and a half mole-equivalents of X2 giving dimers 4a and [Pt2Br2(CO)2(PCy3)2](4b) as well as [Pt2X2(mu-X)2(CO)2(PCy3)2]. Monomers cis-[PtX2(CO)(PCy3)] were the final products of the reaction of with excess of halogens. Insertion of SnCl2 was observed into the Pt-Pt bond but not into the Pt-X bond, when equimolar amounts of SnCl2 x 2H2O were added to a solution of 4a or its chloro-analogue giving [Pt2X2(micro-SnCl2)(CO)2(PCy3)2]. The Pt(I) dimers have unusually small J(Pt-Pt) values as observed by 195Pt NMR and calculated by DFT. These values showed periodic changes comparing 4a and its analogues with other halides and mixed halide dimers.

Journal Article↗

Balancing framework densification with charged, halogen-bonded-pi-conjugated linkages: [PPh4]2{[E-TTF-I2][Re6Se8(CN)6]} versus [PPh4]2[EDT-TTF-I]2{[EDT-TTF-I][Re6Se8(CN)6]}.

The ionic character of a set of two redox linkages and strong, directional halogen bonding at the organic-inorganic interface compromise to produce two materials sharing a common two-dimensional net, eventually extended in a third dimension, although two of the six symmetrical halogen bond acceptors ultimately remain uninvolved as a result of charge densification.

Journal Article↗

Activation of insulin-secreting cells by pyruvate and halogenated derivatives.

Addition of pyruvate to rat islets perifused in the presence of 5 mM-glucose elicited an immediate pronounced biphasic stimulation of insulin secretion. At lower concentrations of glucose (2.5 mM), only the initial, transient, phase of secretion was observed. Pyruvate inhibited 45Ca2+ efflux from islets at 2.5 mM-glucose and stimulated efflux at 5 mM-glucose. Pyruvate also decreased the rate of efflux of 86Rb+ from perifused islets. A marked stimulation of insulin secretion and 45Ca2+ efflux rate was observed in response to 3-fluoropyruvate and 3-bromopyruvate, compounds which inhibited oxidative metabolism of [14C]glucose and [14C]pyruvate in islets. The stimulatory effects of 3-fluoro- and 3-bromo-pyruvate were associated with enhanced 86Rb+ efflux. Withdrawal of pyruvate or halogenated analogues from the perfusate resulted in a secondary stimulation of insulin release, 45Ca2+ efflux and, to some extent, 86Rb+ efflux rates. Pyruvate, 3-fluoropyruvate and 3-bromopyruvate were all effective in promoting intracellular acidification and a rise in cytosolic Ca2+ concentration, as judged from fluorescence measurements in HIT-T15 cells loaded with 2',7'-biscarboxyethyl-5'(6')-carboxyfluorescein and Quin 2 respectively. It is proposed that oxidative metabolism of pyruvate is not a prerequisite for its stimulatory actions on pancreatic beta-cells. An alternative mechanism of activation by pyruvate and its halogenated derivatives is proposed, based on the possible electrogenic flux of these anions across the cell membrane.

Animals↗

Conventional and high-intensity halogen light effects on polymerization shrinkage of orthodontic adhesives.

The objectives of this study were to compare the polymerization shrinkage of three orthodontic adhesives. In addition we wanted to determine the effectiveness of the high-intensity quartz tungsten halogen (HQTH) in curing orthodontic adhesives on polymerization shrinkage with that of the quartz tungsten halogen (QTH). A total of 120 glass ring molds were prepared using a low-speed saw. The internal surface of the glass rings were roughened and etched. Adhesive pastes were placed into the glass molds, which were sandwiched between two glass slides. Samples were divided into six groups according to the combination of three orthodontic adhesives (Kurasper F, Light Bond, and Transbond XT) and two light intensities. One half of each 40 samples of three adhesive pastes was polymerized for 20 seconds by a QTH (Hilux 350), and the other half was polymerized for 10 seconds by a HQTH (Optilux 501). The volumetric polymerization shrinkage for each system was measured through the specific density method modified by Puckett and Smith. Statistical analysis was performed using two-way analysis of variance for intergroup comparisons. The HQTH-curing unit resulted in a more polymerization shrinkage than did the QTH for all investigated adhesives. However, no statistically significant differences were found. The highest shrinkage was observed for Light Bond cured with HQTH (1.59 +/- 0.82%), and the lowest value was observed for Transbond XT cured with QTH (1.23 +/- 0.60%). There are no significant differences in polymerization shrinkage of the three investigated orthodontic adhesives when polymerized with a QTH or a HQTH.

Acid Etching, Dental↗

Formation and properties of halogenated aluminum clusters.

The fast-flow tube reaction apparatus was employed to study the halogenation of aluminum clusters. For reactions with HX (X=Cl, Br, and I), acid-etching pathways are evident, and we present findings for several reactions, whereby Al(n)X(-) generation is energetically favorable. Tandem reaction experiments allowed us to establish that for Al(n)Cl(-), Al(n)I(-), and Al(n)I(2) (-), species with n=6, 7, and 15 are particularly resistant to attack by oxygen. Further, trends in reactivity suggest that, in general, iodine incorporation leaves the aluminum clusters' electronic properties largely unperturbed. Ab initio calculations were performed to better interpret reaction mechanisms and elucidate the characteristics of the products. Lowest energy structures for Al(13)X(-) were found to feature icosahedral Al(13) units with the halogen atom located at the on-top site. The charge density of the highest occupied molecular orbital in these clusters is heavily dependent on the identity of X. The dependence of reactivity on the clusters' charge state is also discussed. In addition, we address the enhanced stability of Al(13)I(-) and Al(13)I(2) (-), arguing that the superhalogen behavior of Al(13) in these clusters can provide unique opportunities for the synthesis of novel materials with saltlike structures.

Journal Article↗

Predication of second-order optical nonlinearity of [(Bu2t Im)AuX] (X=halogen) using time-dependent density-functional theory combined with sum-over-states method.

The dipole polarizability and second-order polarizability of recently synthesized (1,3-di-ter-butylimidazol-2-ylidine) gold complexes [(Bu2t Im)AuX] (X=halogen) were investigated by using time-dependent density-functional theory combined with sum-over-states method. We have discovered that these complexes possess remarkably larger molecular second-order polarizability compared with the organometallic and organic complexes. The value of the second-order polarizability increases in the order of F<Cl<Br<I. The analysis of the molecular orbital suggests that the charge transfer from halogen atom to the carbene ligand plays the key role in nonlinear optical response of gold complexes. The gold of these complexes is a bridge of charge transfer, unlike other organometallic complexes, the metal center may be a strong donor or acceptor. These complexes have a possibility to be excellent second-order nonlinear optical materials from the standpoint of transparency, relatively large beta values and relatively small dispersion behaviors.

Journal Article↗

Thermoluminescent properties of crystalline halogen substituted uracils.

The thermoluminescent properties of crystalline uracil (U), and its halogen-substituted derivatives, 5 bromo-uracil (5BrU), 5 fluorouracil (5FU) and 5 iodo-uracil (5IU), have been investigated. The X-ray-induced thermoluminescent output increases in the order U less than 5 FU less than 5BrU less than 5IU. However, a reversed relationship is found for the U.V.-stimulated thermoluminescence. The thermoluminescence-emission spectra suggest that the same de-excitation process operates in all the halogen-substituted uracils, but the glow curves show that the charge-trapping characteristics are different for each material.

Bromouracil↗

Radiobiology and clinical application of halogenated pyrimidine radiosensitizers.

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.

Bromodeoxyuridine↗

Modification of potentially lethal damage in irradiated Chinese hamster V79 cells after incorporation of halogenated pyrimidines.

Radiosensitization of exponentially growing and plateau phase Chinese hamster V79 cells by incorporation of halogenated pyrimidines (HP) was investigated for different culture conditions that influenced repair. For this purpose cells were grown for 72 h with 0, 1, 2 and 4 microM of chloro-(CldUrd), bromo- (BrdUrd) or iodo-deoxyuridine (IdUrd) and were subsequently irradiated with gamma-rays from a 197Cs source, either in exponential growth or in plateau-phase. Cell survival after irradiation was determined by clonogenic assay. In exponentially growing cultures thymidine-replacement in the DNA of the cells after incubation with 4 microM of CldUrd, BrdUrd and IdUrd was 22.3, 32.7 and 12.7%, respectively. In plateau-phase cultures the percentage thymidine replacement in the DNA of the cells after incubation during growth with 4 microM CldUrd, BrdUrd and IdUrd was 27.5, 33.8 and 10.7%, respectively. Linear-quadratic analyses of the radiation survival curves were performed. In exponentially growing cells a marked increase by a factor 2-3 of the value of alpha was obtained. The beta term significantly increased only in cells which were grown in the presence of BrdUrd and which were trypsinized and replated immediately after irradiation. In plateau-phase cells which were trypsinized and plated immediately after irradiation both alpha and beta increased up to a factor 2-3 with increasing incorporation of halogenated pyrimidines. In plateau phase cells which were allowed to repair potentially lethal damage (PLD) for 6 h and subsequently trypsinized and plated, alpha increased by a factor 3-4. In these latter conditions changes in beta were smaller. In exponentially growing cells in which repair was allowed after irradiation by plating prior to the treatment, the alpha values decreased for all the HP drugs tested as compared to the alpha of cells plated immediately after irradiation. In contrast, delay of plating for plateau phase cells yielded increased alpha values not only when compared with the alpha of plateau phase cells plated immediately after treatment but also when compared with the alpha value of radiosensitized exponentially growing cells. The increase of alpha might be interpreted as an enhancement in the expression of PLD. The larger contribution of fixation of PLD might be due to initial DNA damage and/or to inhibition of PLD repair resulting from incorporation of HP. The increase of beta might be attributed to enhanced interaction or to fixation of sublethal damage (SLD). In view of clinical applications of HP it is of interest that sensitization is not abolished in plateau-phase cells.

Animals↗