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PubMed2006

The efficient direct synthesis of N,O-acetal compounds as key intermediates of discorhabdin A: oxidative fragmentation reaction of alpha-amino acids or beta-amino alcohols by using hypervalent iodine(III) reagents.

Hypervalent iodine(III) reagents are readily available, easy to handle, and have a low toxicity and similar reactivities to those of heavy metal reagents, and hence they are used for various oxidative reactions. The oxidative cleavage of alkynes or carbonyl compounds by using bis(trifluoroacetoxy)iodo(III) pentafluorobenzene (C(6)F(5)I(OCOCF(3))(2)) has been reported. Herein, the efficient direct synthesis of N,O-acetal compounds as key intermediates of discorhabdin A, by the oxidative fragmentation reaction of alpha-amino acids or beta-amino alcohols by using C(6)F(5)I(OCOCF(3))(2), is described.

Amino Acids↗
PubMed2005

Tetrakis(imidazolium) macrocyclic receptors for anion binding.

New (tetrakis)imidazolium macrocyclic receptor systems of variable cavity size have been synthesised by stepwise alkylation reactions of bis(imidazolium) precursor compounds. Proton NMR titration studies reveal the macrocycles to strongly bind halide and benzoate anions, with two receptor systems displaying notable selectivity for fluoride in competitive acetonitrile-water (9:1) solvent media.

Anions↗
PubMed1994

Cyclic enkephalin analogs with exceptional potency at peripheral delta opioid receptors.

A series of super potent and delta-opioid-receptor-selective cyclic hexapeptides of the general formula [formula: see text] (where X is hydrogen or halogen) has been synthesized. The unsubstituted hexapeptide formula; see text: [Phe6]DPLCE) has extremely high potency at peripheral delta opioid receptors (IC50 value in the MVD assay is 0.016 nM) and in bioassays is the most selective compound in this series. The introduction of halogens in the phenyl ring of phenylalanine at position 4 led to significant changes in the selectivity and affinities at peripheral and central opioid receptors. In the binding studies, the most potent compound is the p-fluoro analog, whereas the most selective analog is the p-iodo-substituted peptide.

Amino Acid Sequence↗
PubMed2006

Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models.

The contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a prototype compound of a whole class of halogenated aromatic hydrocarbons termed 'dioxinlike' contaminants present in food, human tissue, mothers milk, and environmental samples. Among the various adverse effects caused by TCDD in animal experiments, its carcinogenic effects caused particular concern. In rodents, long-term TCDD treatment leads to the development of tumors of the liver, thyroid, lung, skin, oral cavity and other sites. The occurrence of liver tumors mainly observed in female rats has been used as a basis for quantitative cancer risk assessment for TCDD. TCDD does not behave like a 'complete carcinogen', i. e. no DNA binding of the parent compound or metabolites thereof could be detected. However, enhanced oxidative damage of hepatic DNA was observed, probably resulting from a dramatic induction of cytochrome P450 enzymes, which are under the regulatory, transcriptional control of the TCDD-activated aryl hydrocarbon receptor. The marked enhancement of TCDD-related oxidative liver DNA damage in rats by estrogens warrants further mechanistic investigation. Furthermore, TCDD acts as a tumor promoter, i. e. it facilitates the growth of putative preneoplastic hepatic lesions after initiation with a complete carcinogen. The mechanisms underlying this effect may be related to altered intracellular signaling involving pronounced changes in the phosphorylation pattern of proteins regulating growth and apoptosis. These effects are thought to result in an enhanced survival of preneoplastic cells, some of which can undergo further steps on the way to malignancy. In summary, a better understanding of the mechanisms of the carcinogenicity of TCDD is mandatory to provide a rational basis for a better inter-species extrapolation. The final aim of these efforts is a more reliable risk assessment for the carcinogenic potency of the class of dioxinlike contaminants in humans.

Animals↗
PubMed2004

X-ray absorption spectroscopic studies on model compounds for biological iodine and bromine.

X-ray absorption spectra of a number of organic iodine and bromine compounds of biological relevance, as well as of a series of iodine compounds with different oxidation states, have been measured. The iodine K-edge spectra (XANES) are found to be relatively featureless but the position of the edge is found to be sensitive to formal valence (among other factors), and the edge shape to the number of bound O atoms. EXAFS spectra of organohalogen compounds (both iodine and bromine) can be used to discriminate between aliphatic and aromatic compounds. There are differences both in the distances from the halogens to the first shell of C atoms, which are shorter for aromatic compounds, and in the patterns of shells in the Fourier transforms. This result is expected to be relevant to studies at these edges in biological systems.

Bromine Compounds↗
PubMed2001

Evaluation of the health risk of platinum group metals emitted from automotive catalytic converters.

A health risk assessment of platinum (Pt) emitted from automotive catalytic converters is presented. Following a stepwise approach, the relevant literature is discussed in order to characterize Pt emissions as well as the toxic potential of Pt and its compounds. In an exposure assessment, ambient Pt concentrations in air are predicted to range from approximately 4 pg/m3 (street canyon, typical conditions) up to approximately 112 pg/m3 (express motorway, severe conditions). These values agree well with the few measured concentrations, which are also in the low pg/m3 range. Pt is emitted from catalytic converters in very small amounts (ng/km range), mainly in the (0)-oxidation state (elemental Pt). The nanocrystalline Pt particles are attached to microm-sized aluminum oxide particles. Whether free ultrafine Pt particles may be emitted and result in biological effects has not been studied sufficiently. Hence, risk assessment can only be based on the respiratory sensitizing potential of halogenated Pt salts. The presence of such compounds in automotive Pt emissions cannot definitely be excluded. From recent occupational studies conducted in catalytic converter production, a conservative no-effect level (NOEL) of 1.5 ng/m3 can be derived for the sensitizing effect of halogenated Pt salts. In a (reasonable) worst case approach, it is assumed that such compounds comprise 1% (0.1%) of the total Pt emissions. Applying a safety factor of 10 to account for interindividual variability, a guidance value of 15 (150) ng/m3 is derived for catalyst-borne Pt. The exposure to Pt in ambient air as measured or predicted is at least two orders of magnitude below this guidance range. Rhodium is also contained in automotive catalysts, palladium has increasingly substituted Pt, and iridium-based catalysts have recently been introduced. Although the database on these platinum group metals is rather small, there is no evidence that they pose a health risk to the general population.

Dose-Response Relationship, Drug↗
PubMed2004

The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells.

Six chemicals, 2-halopropionic acids, thiophene, methylhalides, methylmercury, methylazoxymethanol (MAM) and trichlorfon (Fig. 1), that cause selective necrosis to the cerebellum, in particular to cerebellar granule cells, have been reviewed. The basis for the selective toxicity to these neurones is not fully understood, but mechanisms known to contribute to the neuronal cell death are discussed. All six compounds decrease cerebral glutathione (GSH), due to conjugation with the xenobiotic, thereby reducing cellular antioxidant status and making the cells more vulnerable to reactive oxygen species. 2-Halopropionic acids and methylmercury appear to also act via an excitotoxic mechanism leading to elevated intracellular Ca2+, increased reactive oxygen species and ultimately impaired mitochondrial function. In contrast, the methylhalides, trichlorfon and MAM all methylate DNA and inhibit O6-guanine-DNA methyltransferase (OGMT), an important DNA repair enzyme. We propose that a combination of reduced antioxidant status plus excitotoxicity or DNA damage is required to cause cerebellar neuronal cell death with these chemicals. The small size of cerebellar granule cells, the unique subunit composition of their N-methyl-d-aspartate (NMDA) receptors, their low DNA repair ability, low levels of calcium-binding proteins and vulnerability during postnatal brain development and distribution of glutathione and its conjugating and metabolizing enzymes are all important factors in determining the sensitivity of cerebellar granule cells to toxic compounds.

Animals↗
PubMed1991

Preparation and biological activity of 2-[4-(thiazol-2-yl)phenyl]propionic acid derivatives inhibiting cyclooxygenase.

A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.

Animals↗
PubMed1968

Biochemical studies of toxic agents. The isolation of premercapturic acids from the urine of animals dosed with chlorobenzene and bromobenzene.

1. A premercapturic acid, i.e. a compound that yields a mercapturic acid when decomposed by acid, was isolated as a dicyclohexylammonium salt from the urine of rats and rabbits that had been dosed with bromobenzene. 2. Another premercapturic acid was isolated as its dicyclohexylammonium salt from the urine of rats that had been dosed with chlorobenzene. 3. When decomposed by acid, the premercapturic acid from the urine of animals dosed with bromobenzene gave p-bromophenylmercapturic acid, m-and p-bromophenol and NN'-diacetylcystine. 4. The premercapturic acid derived from chlorobenzene gave the corresponding chloro compounds together with NN'-diacetylcystine when decomposed by acid. 5. On the basis of these and other observations it is suggested that the premercapturic acid formed in the metabolism of bromobenzene is N-acetyl-S-(4-bromo-1,2-dihydro-2-hydroxyphenyl)-l-cysteine. 6. It is also suggested that the premercapturic acid derived from chlorobenzene has an analogous structure.

Animals↗
PubMed1982

Chloroperoxidase halogenation reactions. Chemical versus enzymic halogenating intermediates.

In the absence of organic substrates, chloroperoxidase catalyzes the peroxidation of chloride and bromide ion to molecular chlorine and bromine. However, these molecular species are not formed as intermediates in the enzymic halogenation of organic halogen-acceptor substrates. The rate of oxidation of chloride to its respective molecular species is considerably slower than the rate of enzymic chlorination of acceptor substrates. Furthermore, differences are observed in substrate specificities between enzymic and chemical halogenation reactions. Thiourea and methionine are substrates in chloride-dependent oxidation reactions catalyzed by chloroperoxidase and are preferred at least 50:1 and 30:1 respectively over 2- chlorodimedone. Corresponding nonenzymic reaction preferences for the oxidation of thiourea versus 2-chlorodimedone chlorination are only 2:1 with hypochlorite and 3:1 with molecular chlorine. Also, hypochlorite shows essentially no preference for methionine compared with 2-chlorodimedone. In the bromide-dependent reactions catalyzed by chloroperoxidase, bromine is formed at a rate equivalent to that of the bromination of acceptor substrates. However, the specificity of the bromide-dependent oxidation of methionine versus the bromination of 2-chlorodimedone by chloroperoxidase is 4:1. This value is significantly higher than the ratio in reactions of these two substrates with molecular bromine, which is essentially 1:1. A general reaction scheme for all reactions of chloroperoxidase with its halogen-acceptor substrates is proposed. This process involves the initial formation of Compound I and its subsequent conversion into an iron (III) hypohalite halogenating intermediate.

Chloride Peroxidase↗
PubMed1984

Technetium-99m benzimidazolyl iminodiacetic acid hepatobiliary radiopharmaceuticals: structure biodistribution studies.

The biodistribution of fifteen structural variants of the hepatobiliary radiopharmaceutical, technetium-99m benzimidazolyl iminodiacetic acid (BIMIDA) were determined 1 h after i.v. injection into rats. The best compounds with respect to hepatobiliary excretion were those with halogen substituents in the benzene ring of the BIMIDA ligand. The cholescintigraphic properties of the BIMIDA compounds compared favourably with those of technetium-99m acetanilido iminodiacetic acid (HIDA) radiopharmaceuticals.

Animals↗
PubMed2005

Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates.

A series of ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates, 8a-11v, were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The selective indexes of inhibition on replication of HBV DNA of compounds 11s (>8.7) and 11t (10.8), which were introduced halogen on the phenyl ring at position 2, were greater than those of the other evaluated compounds including lamivudine (7.0). Compounds 9e, 9h, 9l, and 11v exhibited significant anti-HBV activities, and the IC(50) values on replication of HBV DNA of these compounds were 3.6, 6.37, 5.2, and 5.4 microg/ml, respectively, which were far more potent than the positive control lamivudine 228 microg/ml.

Antiviral Agents↗
PubMed2004

Titanocene modulation of cytokine imbalance induced by Ehrlich ascites tumour progression.

In the present work, we have studied the effects of two titanocenes, biscyclopentadienyldichlorotitanium IV (DDCT) and its derivative, biscyclopentadienylditiocianatetitanium IV (BCDT), on the production of cytokines [interferon-gamma (IFN-gamma), interelukin-1, interleukin (IL) 2, IL-4, and IL-10] by concanavalin A (Con A)-stimulated T cells obtained from Ehrlich ascites tumour (EAT)-bearing BALB/c mice. The treatment consisted of intraperitoneal (i.p) administration of 15 mg/kg/day DDCT for 2 days or 10 mg/kg/day BCDT for 3 days. We observed that the levels of IFN-gamma, but not IL-2, were dramatically increased in the early phase of EAT development. With tumour evolution, however, a sharp and progressive decrease in the levels of both IFN-gamma and IL-2 was found concomitantly to an enhancement in the levels of IL-10. Treatment of these mice with both titanocene compounds demonstrated that DDCT is more effective in modulating the cytokine imbalance induced by the tumour since it could prevent the early enhancement of IFN-gamma, the late decline of IFN-gamma and IL-2, and the increase in the IL-10. The administration of BCDT, in spite of preventing early IFN-gamma enhancement and increase in IL-10, did not produce any change in the IL-2 levels and did not prevent the decline of IFN-gamma levels during tumour evolution. Collectively, these results reveal that the ability of titanocenes to reverse tumour-induced immunosuppression and delay tumour growth is more evident in the DDCT compound, thus indicating that the substitution of the halides halogens by pseudohalogens, present in the molecular structure of BCDT, leads to a less effective antitumoral compound.

Animals↗
PubMed1984

Design, synthesis, and testing of potential antisickling agents. 4. Structure-activity relationships of benzyloxy and phenoxy acids.

In this paper we further establish the activity of two classes of small molecules, benzyloxy and phenoxy acids, as potent inhibitors of hemoglobin S (HbS) gelation. Structural modifications with a large number of each class confirm our earlier work that the highest activity is observed with compounds that contain dihalogenated aromatic rings with attached polar side chains. We have also found a halogenated aromatic malonic acid derivative to be quite active. Compounds reported in this paper are compared with other antigelling agents studied in our laboratory. Comments are made concerning the antigelling activity and binding sites of four derivatives and their effect on the allosteric mechanism of hemoglobin (Hb) function.

Acetates↗
PubMedDate not supplied

DOTA-D-Tyr(1)-octreotate: a somatostatin analogue for labeling with metal and halogen radionuclides for cancer imaging and therapy.

The goal of this study was to evaluate a somatostatin receptor ligand, DOTA-D-Tyr(1)-octreotate (DOTA-DY1-TATE), that has the chelator 1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'"-tetraacetic acid (DOTA) attached to the D-Tyr(1) residue, allowing radiolabeling with both radiohalogens and radiometals. A potential advantage of having a chelator attached to the Tyr(1) residue is that halogen radiolabels may residualize or remain trapped in tumor cells rather than clear from the tumor. DOTA-DY1-TATE was synthesized by solid-phase methods and radiolabeled with (61)Cu, (64)Cu, and (125)I in high radiochemical purity and specific activity. A competitive binding assay demonstrated that (nat)Cu-DOTA-DY1-TATE and DOTA-(nat)I-DY1-TATE had comparable affinity to (nat)In-DTPA-OC in AR42J rat pancreatic tumor cells membranes. (61)Cu-DOTA-DY1-TATE had a dissociation constant (K(d)) of 176.4 pM and a receptor concentration (B(max)) of 244.4 fmol/mg. A tumor uptake of 1.515 %ID/g was determined for (64)Cu-DOTA-DY1-TATE and 0.814 %ID/g for DOTA-(125)I-DY1-TATE in AR42J tumor bearing Lewis rats at 1 h postinjection. DOTA-(125)I-DY1-TATE remained in the tumor at a higher concentration out to 4 h postinjection, suggesting that the iodine may have residualized in the tumor cells. MicroPET imaging of (64)Cu-DOTA-DY1-TATE in AR42J tumor bearing rats and SCID mice at 2 h postinjection showed significant uptake and good contrast in the thigh tumors in the rat model and in the neck and thigh tumors of the mouse. This study demonstrates that DOTA-DY1-TATE is a somatostatin analogue that can be labeled with both metal and halogen radionuclides, and its (64)Cu- and (125)I-radiolabeled compounds showed somatostatin receptor-mediated uptake in normal and tumor tissues.

Animals↗