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Intramolecular chiral recognition in electron-transfer-induced fluorescence quenching has been observed for diastereomeric dyads composed of a naphthalene chromophore and an amine.
Concentrations of polychlorinated naphthalene (PCN) congeners were measured in domestic animal related samples such as feed ingredients, mixed feed and animal fat. Mean concentrations of total PCNs in feed ingredients ranged from 500 to 1500 pg g(-1) lipid wt with a high concentration found in fish meal. Total PCN concentrations were similar among mixed feeds, which ranged from 98 to 110 pg g(-1) lipid wt. The total PCN concentration in chickens was more than twice the amount in pigs. Tetra-CNs were the predominant homologues in all samples. Biomagnification of higher chlorinated PCN congeners, especially penta- and hexa-CNs, was a few fold greater in chickens compared to pigs. The estimated concentrations of 2,3,7,8-tetrachloro dibenzo-p-dioxin equivalents (TEQs) of some selected PCNs in feed ingredients, mixed feeds, chickens and pigs were 0.008 to 0.063, 0.001 to 0.002, 0.033 and 0.011 pg g(-1) lipid wt, respectively. Based on predicted luciferase inducing potency for each PCN congener, the estimated PCN-TEQs in feed ingredients and animal fat were similar to those that were estimated from selected PCNs.
Two dyads containing a naphthalene-like chromophore linked to a pyrrolidine-derived moiety, namely (S,S)- and (R,S)-NPX-PYR, have been synthesised by esterification of (S)- or (R)-naproxen (NPX) with (S)-N-methyl-2-pyrrolidinemethanol (PYR) and submitted to photophysical studies (steady-state and time-resolved fluorescence, as well as laser flash photolysis). The emission spectra of the dyads in acetonitrile were characterised by a typical band centred at 350 nm, identical to that of the reference compound (S)-NPX. However the intensities were clearly different, revealing a significant intramolecular quenching in the dyads, as well as a remarkable stereodifferentiation (factor of 1.6). Accordingly, the fluorescence lifetimes of the two dyads were different from each other and markedly shorter than that of (S)-NPX. The quenching mechanism is intramolecular electron transfer, that is thermodynamically favoured. Exciplex formation, that is nearly thermoneutral, does not compete efficiently. The electron transfer rate constants for (S,S)- and (R,S)-(NPX-PYR) were 1.8 x 10(8) and 2.8 x 10(8) s(-1), respectively. By contrast, no significant intramolecular quenching was observed for the excited triplet states (lambda(max)= 440 nm), generated by laser flash photolysis; this is in agreement with the fact that intramolecular electron transfer is thermodynamically disfavoured, due to the lower energy of excited triplets.
A simple, highly efficient and cheap synthesis of substituted naphthalenes is reported. These aromatic compounds can be easily prepared in acidic or basic conditions from [small alpha]-tetralones, obtained by a xanthate-mediated addition-cyclisation sequence.
An efficient regioselective naphthoannulation strategy able to fuse a newly formed naphthalene ring at its 1,2- and 3,4- positions to two different heterocycles has been developed.
During the anaerobic biodegradation of naphthalene and methylnaphthalene, unique metabolites are formed by specific microbial carboxylation and ring-reduction reactions. Groundwater samples from an anoxic, shallow aquifer contaminated with gasoline were examined for the presence of these metabolites by extraction, derivatization and gas chromatography coupled to mass spectroscopy. Several metabolites [2-naphthoic acid (2-NA), tetrahydro-2-naphthoic acid (TH-2-NA), hexahydro-2-naphthoic acid (HH-2-NA) and methylnaphthoic acid (MNA)] were found to be present in the groundwater samples. The concentration of 2-NA at each monitoring well was quantified and correlated to the zones of contamination. The presence of the other metabolites in the same wells as 2-NA was used as confirmation that the anaerobic pathway was indeed active. The distribution of metabolites at this site shows that they can be used as biomarkers for demonstrating in situ biodegradation.
alpha-Acetylamino naphthalene (1) was reacted with different aromatic aldehydes and with primary or secondary amines to give alpha-aminonaphthylsubstitutedaryl chalkones (2-5) and alpha-(substituted aminoethyl)-amidonaphthalenes (14-25), respectively. These substituted chalkones were treated with hydrazinehydrate and hydroxylamine hydrochloride to give 1-acetyl-5-substitutedaryl-3-(alpha-aminonaphthyl)-2-pyrazolines (6-9) and alpha-(2-substitutedaryl-isoxazolin-4-yl)-aminonaphthalenes (10-13), respectively. Their chemical structures were confirmed by IR and 1H-NMR spectral data and elemental analysis. Studies of the anti-inflammatory and ulcerogenic activities and acute toxicity of these newly synthesized compounds were performed in vivo and compared with the standard drug, phenylbutazone (CAS 50-33-9). Some of these compounds showed potent anti-inflammatory activity and less ulcerogenic effects than phenylbutazone.
This work reports a genetic analysis of the interactions between NahR, the LysR-type regulator of the NAH operons for biodegradation of naphthalene in Pseudomonas, and its aromatic effectors. Six mutants encoding NahR variants responsive to salicylate analogs such as benzoate, which is not an inducer for the wild type regulator, were isolated with a polymerase chain reaction-based saturation mutagenesis protocol. Most mutants displaying a specific change of effector profile bore single amino acid substitutions within a short protein segment of 60 residues located at the central portion of the NahR sequence. Some of the protein variants exhibited an increased affinity for salicylate and also for otherwise suboptimal effectors, with apparent Ks' values 5-100-fold lower than those of the wild type NahR protein. In addition, all mutants were activated by inducers bearing novel substituents at positions 1 or 2 of the aromatic ring and displayed also an enhanced tolerance to changes at positions 3 and 4. Correlation between mutations in NahR and the structures of the new effectors suggested that protein sites Met116, Arg132, Asn169, and Arg248 are involved in effector recognition and binding during the earlier steps of the process leading to transcriptional activation of cognate NAH promoters.
A novel thermostable Mn(II)-dependent 2,3-dihydroxybiphenyl-1,2-dioxygenase (BphC_JF8) catalyzing the meta-cleavage of the hydroxylated biphenyl ring was purified from the thermophilic biphenyl and naphthalene degrader, Bacillus sp. JF8, and the gene was cloned. The native and recombinant BphC enzyme was purified to homogeneity. The enzyme has a molecular mass of 125 +/- 10 kDa and was composed of four identical subunits (35 kDa). BphC_JF8 has a temperature optimum of 85 degrees C and a pH optimum of 7.5. It exhibited a half-life of 30 min at 80 degrees C and 81 min at 75 degrees C, making it the most thermostable extradiol dioxygenase studied. Inductively coupled plasma mass spectrometry analysis confirmed the presence of 4.0-4.8 manganese atoms per enzyme molecule. The EPR spectrum of BphC_JF8 exhibited g = 2.02 and g = 4.06 signals having the 6-fold hyperfine splitting characteristic of Mn(II). The enzyme can oxidize a wide range of substrates, and the substrate preference was in the order 2,3-dihydroxybiphenyl > 3-methylcatechol > catechol > 4-methylcatechol > 4-chlorocatechol. The enzyme is resistant to denaturation by various chelators and inhibitors (EDTA, 1,10-phenanthroline, H2O2, 3-chlorocatechol) and did not exhibit substrate inhibition even at 3 mm 2,3-dihydroxybiphenyl. A decrease in Km accompanied an increase in temperature, and the Km value of 0.095 microm for 2,3-dihydroxybiphenyl (at 60 degrees C) is among the lowest reported. The kinetic properties and thermal stability of the native and recombinant enzyme were identical. The primary structure of BphC_JF8 exhibits less than 25% sequence identity to other 2,3-dihydroxybiphenyl 1,2-dioxygenases. The metal ligands and active site residues of extradiol dioxygenases are conserved, although several amino acid residues found exclusively in enzymes that preferentially cleave bicyclic substrates are missing in BphC_JF8. A three-dimensional homology model of BphC_JF8 provided a basis for understanding the substrate specificity, quaternary structure, and stability of the enzyme.
Chlorinated naphthalenes (CNs) and chlorinated biphenyls (CBs), hexachlorobenzene (HCB), and p,p'-DDE were determined in human adipose and liver tissues collected at autopsy of 5 men and 2 women (Swedish), 47-80 yr of age. In paired adipose tissue and liver samples, the differences of the distribution of CNs, CBs, HCB, and p,p'-DDE were small, but the concentrations of the compounds (lipid weight basis) varied between the subjects. Generally, the profiles of the contaminants were similar in the subjects. However, in one of the male subjects (80 yr of age) the concentrations of 1,2,3,5,7/1,2,4,6,7-pentaCN and 1,2,3,4,6,7/1,2,3,5,6,7-hexaCN were much higher in the liver: 6 and 20 times higher than in adipose tissue, respectively. The concentration of the toxic coplanar 3,3',4,4',5-pentaCB (CB-126) was also high in the liver from this individual, three times higher concentration than in adipose tissue. It is suggested that the multiplicity of contaminants found in humans should be taken into consideration in risk assessment and that further studies are needed on the distribution of contaminants in different tissues.
The results of a study of the potential migration of diisopropyl naphthalenes (DIPN) from recycled paperboard packaging into some types of dry solid foodstuffs are reported. Paperboard diskettes containing different DIPN concentrations were prepared and put into contact with four types of dry solid foodstuffs, having high specific surface areas and different lipid contents. At regular intervals the DIPN content in the foods was determined. Two migration mechanisms have been proposed and verified. The first one relates to the direct contact existing between paperboard and foodstuff. The second one refers to the indirect contact between paperboard and food, controlled by an air space created above the paperboard into which the DIPN has diffused. Both mechanisms occurred and the migration depended on different factors: the contact time, the characteristics of the foodstuffs and the DIPN content in the cellulose-based matrix. However, only very low levels of contamination in the foodstuffs occurred in migration. As a consequence, this report also considers possible limitations which could be applied to the content of carbonless copy paper in packaging paperboard formulations.
Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimental for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.
Some 6-fluoro-5-substituted-benzimidazole derivatives in which indole and 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene groups were attached to the 2-position of the benzimidazole ring were synthesized and tested for antioxidant properties in vitro. Almost all the synthesized compounds at the 10(-3) M concentrations showed superoxide anion scavenging activity. Compounds 5, 3, 9, 4, 17 and 13 have strong inhibitory effects on superoxide anion formation (98%, 93%, 91%, 88%, 85% and 81%, respectively) at 10(-3) M concentration and these results are better than 30 IU of superoxide dismutase (SOD) (76%). Compound 11 is the most effective scavenger of 2,2-diphenyl-1-picrylhydrazyl (DPPH) stable free radical at 10(-3)M (61%) concentration.
When the synthetic hydroxyl radical generator, N, N'-bis (2-Hydroperoxy-2-methoxyethyl)-1,4,5,8-naphthalene-tetracarboxylic diimide, NP III, was photoirradiated in the presence of ferric-cytochrome c (Fe3+), the fragmentation peak corresponding to the specific oxidative modification at the histidine site of cytochrome c was observed in the Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectroscopy (MALDI-TOF) measurement. Without photoirradiation, no such protein oxidation was observed in the experimental conditions employed. This result suggests the possible usage of NP-III as an oxidative protein-modifying reagent.
Ethylene glycol dimethyl ether (EGdiME), diethylene glycol dimethyl ether (diEGdiME), triethylene glycol dimethyl ether (triEGdiME), diethylene glycol diethyl ether (diEGdiEE), ethylenethiourea (ETU), sodium selenite (SS), dimethyl phthalate (DMP), naphthalene (NAP), or p-nitrophenol (PNP) were administered by gavage for eight consecutive days to female CD-1 mice. Weight loss was insensitive as an index of sublethal adult toxicity and was inadequate for determining a maximum tolerated dose. LD50 values indicate that SS, NAP, and PNP were more toxic (8.4, 353.6, and 625.7 mg/kg, respectively) than the polyglycol ethers, ETU, and DMP (LD50 values ranged from 2525.8 to 6281.9 mg/kg). Each of the compounds was administered on d 7 through 14 to pregnant animals at a single dose estimated to be at or just below the threshold of adult lethality. In such a reproductive study, each of the compounds could be categorized on the basis of the pattern of maternal lethality and fetotoxicity which it produced. The number of dams with complete resorptions was significantly increased after administration of ETU, and no mice in the EGdiME-, diEGdiME-, or triEGdiME-treated groups delivered any viable offspring. Maternal lethality was significant in the EGdiME, triEGdiME, PNP, and NAP groups. There was a slight reduction in the average number of live pups per litter in the diEGdiEE- and PNP-treated groups and a significant reduction in the NAP group. The number dead per litter was increased with diEGdiEE. SS and DMP had no effect on maternal or fetal survival at the doses administered. Individual pup weight at d 1 postpartum was only significantly reduced by diEGdiEE, and no gross congenital abnormalities were detected in neonates from any treatment group. These results provide guidelines for the subsequent toxicity testing of these chemicals.
The lung, which is in intimate contact with the external environment, is exposed to a number of toxicants both by virtue of its large surface area and because it receives 100% of the cardiac output. Lung diseases are a major disease entity in the U.S. population ranking third in terms of morbidity and mortality. Despite the importance of these diseases, key issues remain to be resolved regarding the interactions of chemicals with lung tissue and the factors that are critical determinants of chemical-induced lung injury. The importance of cytochrome P450 monooxygenase dependent metabolism in chemical-induced lung injury in animal models was established over 25 years ago with the furan, 4-ipomeanol. Since then, the significance of biotransformation and the reasons for the high degree of pulmonary selectivity for a myriad of different chemicals has been well documented, mainly in rodent models. However, with many of these chemicals there are substantial differences in the susceptibility of rats vs. mice. Even within the same species, varied levels of the respiratory tract respond differently. Thus, key pieces of data are still missing when evaluating the applicability of data generated in rodents to primates, and as a result of this, there are substantial uncertainties within the regulatory community with regards to assessing the risks to humans for exposure to some of these chemicals. For example, all of the available data suggest that the levels of cytochrome P450 monooxygenases in rodent lungs are 10-100 times greater than those measured in the lungs of nonhuman primates or in man. At first glance, this suggests that a significant margin of safety exists when evaluating the applicability of rodent studies in the human, but the issues are more complex. The intent of this review is to outline some of the work conducted on the site and species selective toxicity and metabolism of the volatile lung toxic aromatic hydrocarbon, naphthalene. We argue that a complete understanding of the cellular and biochemical mechanisms by which this and other lung toxic compounds generate their effects in rodent models with subsequent measurement of these cellular and biochemical events in primate and human tissues in vitro will provide a far better basis for judging whether the results of studies done in rodent models are applicable to humans.
Repeated exposures to bioactivated cytotoxicants such as naphthalene (NA) render the target population, Clara cells, resistant to further injury through a glutathione-dependent mechanism. The current studies were designed to test the hypothesis that the mechanism for tolerance is localized in Clara cells. We used three approaches to test this hypothesis. First, using airway explants from tolerant mice maintained in culture, we sought to determine if the mechanism of Clara cell tolerance was airway-specific. Second, using inhalation as the route of exposure, we sought to determine if Clara cells at all airways levels become tolerant to repeated inhalation exposures of NA. Third, by measuring gamma-glutamylcysteine synthetase (gamma-GCS) activity and expression we determined if tolerance to inhaled NA resulted from shifts in phase-II metabolism. Our results indicate that Clara cells in explants from tolerant mice remained tolerant to NA injury in culture. When mice were exposed to repeated inhalation exposures of NA (15 ppm), we found that Clara cells at all airway levels became tolerant. Expression and activity analysis revealed that gamma-GCS, the rate-limiting enzyme in glutathione synthesis, is induced in tolerant Clara cells. Buthionine sulfoximine, a gamma-GCS inhibitor, was able to eliminate the resistance of these tolerant cells. We conclude: (1) the mechanism of NA tolerance in Clara cells is airway specific, (2) the specific mechanism allows Clara cells to become tolerant to NA vapor at levels relevant to human exposure, and (3) the mechanism of tolerance to inhaled NA is highly dependent on induction of the catalytic enzyme, gamma-GCS.
Identification of soft tissue sarcomas (STSs) in epidemiologic mortality studies is complicated by nosologic coding rules that require that STSs arising in a visceral organ must be coded in the International Classification of Diseases (ICD) category for that organ, rather than in the ICD category for malignant neoplasms of connective tissue. Moreover, prior studies have shown poor agreement between diagnoses recorded on death certificates compared with those in hospital records for these tumors. We reviewed deaths from STS among workers in a registry of 6,716 dioxin-exposed workers at the National Institute for Occupational Safety and Health (NIOSH) and in a NIOSH cohort mortality study of 10,240 workers exposed to chlorinated naphthalenes. We identified 19 subjects with STSs. Of these, 17 (89%) were identifiable by reading the entries on selected death certificates, and two (11%) were found only by reviewing medical records of cases coded to ICD categories likely to have contained STS. Of the 17 STSs identified from death certificates, only nine (53%) had been coded as underlying cause of death to the ICD category "malignant neoplasms of soft and connective tissue." Medical records were obtained for 14 of the 17 cases (82%), and in each case, the STS diagnosis was verified. Tissue blocks from tumors were available for review in nine of the 17 cases identified from death certificates, and the diagnosis of STS was verified in seven (78%). Nosologic rules reduce the sensitivity of cohort mortality studies to detect excesses of STS.(ABSTRACT TRUNCATED AT 250 WORDS)