Kåre B. Jørgensen

Photochemical oxidative cyclisation of stilbenes and stilbenoids : the Mallory-reaction

After Mallory described in 1964 the use of iodine as catalyst for the photochemical cyclisation of stilbenes, this reaction has proven its effectiveness in the synthesis of phenanthrenes, other PAHs and phenacenes with a surprisingly large selection of substituents. The “early age” of the reaction was reviewed by Mallory in 1984in a huge chapter in the Organic Reactions series, but the development has continued. Alternative conditions accommodate more sensitive substituents, and isomers can be favoured by sacrificial substituents. Herein the further developments and applications of this reaction after 1984 are discussed and summarized.

Ultrasound-assisted synthesis of novel 1,2,3-triazoles coupled diaryl sulfone moieties by the CuAAC reaction, and biological evaluation of them as antioxidant and antimicrobial agents.

A series of 1,2,3-triazoles coupled diaryl sulfone containing compounds were synthesized by the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction in benign solvents under ultrasound irradiation. In situ formation of azides from α-bromoketones together with the CuAAC reaction in one pot allowed safe handling and good availability of azides for the development of a small library of compounds. The sonication reduced reaction time and increased yields compared to otherwise same conditions. All synthesized compounds were evaluated for antibacterial, antifungal and antioxidant activities. Compounds 3b, 6b and 9e-9g were found to be the most potent antifungal agents with minimal inhibitory concentration (MIC) at 25 μg/mL; moreover other compounds revealed good to moderate antimicrobial activity. Compound 8e showed an excellent antioxidant activity using a DPPH free radical scavenging assay.

Quantitative structure–activity relationships for chronic toxicity of alkyl-chrysenes and alkyl-benz[a]anthracenes to Japanese medaka embryos (Oryzias latipes)

Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are a class of compounds found at significant concentrations in crude oils, and likely the main constituents responsible for the chronic toxicity of oil to fish. Alkyl substituents at different locations on the aromatic rings change the size and shape of PAH molecules, which results in different interactions with tissue receptors and different severities of toxicity. The present study is the first to report the toxicity of several alkylated derivatives of chrysene and benz[a]anthracene to the embryos of Japanese medaka (Oryzias latipes) using the partition controlled delivery (PCD) method of exposure. The PCD method maintained the desired exposure concentrations by equilibrium partitioning of hydrophobic test compounds from polydimethylsiloxane (PDMS) films. Test concentrations declined by only 13% over a period of 17 days. Based on the prevalence of signs of blue sac disease (BSD), as expressed by median effective concentrations (EC50s), benz[a]anthracene (B[a]A) was more toxic than chrysene. Alkylation generally increased toxicity, except at position 2 of B[a]A. Alkyl-PAHs substituted in the middle region had a lower EC50 than those substituted at the distal region. Except for B[a]A and 7-methylbenz[a]anthracene (7-MB), estimated EC50 values were higher than their solubility limits, which resulted in limited toxicity within the range of test concentrations. The regression between log EC50s and logKow values provided a rough estimation of structure-activity relationships for alkyl-PAHs, but Kow alone did not provide a complete explanation of the chronic toxicity of alkyl PAHs.

Directed Metalation–Suzuki–Miyaura Cross-Coupling Strategies: Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes

A general, efficient, and regioselective synthesis of a series of hydroxylated 1-methylphenanthrenes 9 by a combined directed ortho metalation (DoM)-Suzuki-Miyaura cross-coupling-directed remote metalation (DreM) sequence is reported. Diversity to this methodology was achieved by a regioselective DoM rather than DreM reaction, affording more highly substituted phenanthrols ( Table 2 ). Application of the turbo-Grignard reagent (i-PrMgCl·LiCl) in the Ni-catalyzed Corriu-Kumada reaction gave efficient decarbamoylation ( Tables 3 and 4 ). Additional features are the TMS protecting group and halo-induced ipso-desilylation tactics applied to the regioselective synthesis of phenanthrenes ( Scheme 2 ).

Characterization of alkylphenol metabolites in fish bile by enzymatic treatment and HPLC-fluorescence analysis.

Alkylphenol (AP) metabolites were characterized in the bile of Atlantic cod (Gadus morhua L.) after exposure to nine individual compounds (10mg/kg fish), 2-methylphenol (2-MP), 4-methylphenol (4-MP), 3,5-dimethylphenol (3,5-DMP), 2,4,6-trimethylphenol (2,4,6-TMP), 4-tert-butylphenol (4-t-BP), 4-tert-butyl-2-methylphenol (4-t-B-2-MP), 4-n-pentylphenol (4-n-PP), 4-n-hexylphenol (4-n-HexP) and 4-n-heptylphenol (4-n-HepP), and a mixture (total dose; 13.5 mg/kg fish) of the nine APs by inter-muscular injection. The degree of alkylation ranged from methyl (C1) to heptyl (C7) and represents the types of APs present in produced water. Fish bile was collected on day 4 and 16 (exposure groups 2-MP, 3,5-DMP, 2,4,6-TMP and 4-t-B-2-MP) following exposure. Characterization of major metabolites was accomplished by enzymatic de-conjugation and analysis by high performance liquid chromatography connected to a fluorescence detector (HPLC-F) acquiring at ex/em 222/306 nm. Two solid phase extraction (SPE) columns were evaluated for clean-up of samples prior to analysis. Independent of alkyl homologue, the glucuronide conjugated APs were the most abundant metabolites (73-100%), whereas sulfates, glucosides and unchanged compounds were excreted in amounts of 0-21%, 0-6.1% and 0-6.3%, respectively. The total concentration of measured metabolites in the bile, determined as their respective APs after de-conjugation, increased with increasing degree of alkylation (3.2+/-2.6 microg/g bile for 2-MP and 571+/-81 microg/g bile for 4-n-HepP) after exposure to an equal dose of AP. Comparison of metabolite concentrations in bile sampled 4 and 16 days after exposure, showed that the levels of 2-MP, 2,4,6-TMP and 4-t-B-2-MP were reduced by 55%, 30% and 45%, respectively whereas 3,5-DMP increased by 25% (not significant). This study suggests that analysis of de-conjugated metabolites in fish bile can be used to monitor AP exposure to fish, due to the relatively high and persistent level of these compounds. However, although HPLC-F is suitable for laboratory exposures, it might not be sufficient selective for field studies.

Polycyclic Aromatic Acids Are Primary Metabolites of Alkyl-PAHs—A Case Study with Nereis diversicolor

Although concentrations of alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) in oil-contaminated sediments are higher than those of unsubstituted PAHs, only little attention has been given to metabolism and ecotoxicity of alkyl-PAHs. In this study we demonstrated that metabolism of alkyl-PAHs primarily forms polycyclic aromatic acids (PAAs). We generalize this to other alkyl-PAHs, based on literature and the present study of the metabolism of 1-methylphenanthrene, 3,6-dimethylphenanthrene, and 1-, 2-, 3-, and 6-methylchrysene related to their unsubstituted parent PAHs. Also, we observed that body burdens and production of PAAs was related to the position of the methyl group, showing the same isomer specific preferences as for microbial degradation of alkyl-PAHs. We detected a high production of PAAs, and larger metabolism of alkyl-PAHs than their unsubstituted parent PAHs. We therefore propose that carboxylic acid metabolites of alkyl-PAHs have the potential of constituting a new class of contaminants in marine waters that needs attention in relation to ecological risk assessments.

Measurement of glycated albumin in serum and plasma by LC-MS/MS

Abstract Background Diagnosis of diabetes and monitoring of long-term blood sugar are preferably done by measurement of glycated hemoglobin (HbA1c). Diabetic patients with end stage renal disease (ESRD) may have short-lived red blood cells due to hemodialysis (HD), and thus higher turnover of hemoglobin. The level of glycated hemoglobin (HbA1c) may be lower than expected for these patients, even at increased blood glucose, possibly making glycated albumin (GA) measurement a better alternative. Methods The percentage of GA was measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Fast and efficient trypsin digestion of proteins in diluted serum or plasma resulted in a high number of proteotypic peptides from albumin, including KQTALVELVK which was detected both glycated and non-glycated by multiple reaction monitoring (MRM). The percentage of GA was estimated by neat peak area response of glycated peptide divided by the sum of glycated and non-glycated peptide. Results Acceptable method reproducibility (6% CV), repeatability (2–6% CV), limit of quantification (0.75% GA), linearity (R2 = 0.999) and recovery (79 ± 9%) was achieved without using calibration or isotope-labeled internal standard. GA was strongly correlated with HbA1c (r = 0.84) for patients without ESRD. The average ratio of GA/HbA1c was significantly higher (p = 0.0021) for ESRD patients (1.84 ± 0.38, n = 62) compared to other patients (1.67 ± 0.28, n = 225). Conclusion GA measurement by detecting glycation in KQTALVELVK with LC-MS/MS seems to be a useful supplement to HbA1c for detecting increased blood glucose in diabetic patients with ESRD.

Efficient stereoselective preparation of protected isodityrosines

Abstract A method for stereoselective preparation of isodityrosines with identical and orthogonal protecting groups is reported. The isodityrosines holding identical protecting groups were prepared from isovaniline in a three step procedure, in 50–64 % yield (> 98% ee, 84–96% de). Isodityrosine holding four orthogonal groups was prepared in four steps from isovaniline in 20 % total yield (> 98% ee, 87% de).

Photochemical synthesis of chrysenols

Chrysenols are formed together with other metabolites when chrysene is metabolized in living organisms. The principal metabolites are needed as pure compounds for reference materials and standards to study various aspects of this metabolism. In this study the 1-, 2-, 3-, and 4-chrysenols have been made in pure form by photochemical ring closure of [(methoxyphenyl)vinyl]naphthalene to the methoxychrysenes followed by deprotection, and purification of the chrysenols. The method may be applied to make the single pure compounds in high yields.

Biological effects of polycyclic aromatic hydrocarbons (PAH) and their first metabolic products in in vivo exposed Atlantic cod (Gadus morhua)

ABSTRACT The monitoring of the presence of polycyclic aromatic hydrocarbons (PAH) in the aquatic environment is a worldwide activity since some of these compounds are well-established carcinogens and mutagens. Contaminants in this class are in fact regarded as priority hazardous substances for environmental pollution (Water Framework Directive 2000/60/EC). In this study, Atlantic cod (Gadus morhua) was selected to assess in vivo effects of two PAH and their first metabolic products, namely, the corresponding trans-dihydrodiols, using biological markers. Fish were exposed for 1 wk to a single PAH (naphthalene or chrysene) and its synthetic metabolites ((1R,2R)-1,2-dihydronaphthalene-1,2-diol and (1R,2R)-1,2-dihydrochrysene-1,2-diol) by intraperitoneal injection in a continuous seawater flow system. After exposure, PAH metabolism including PAH metabolites in bile and ethoxyresorufin O-deethylase (EROD) activity, oxidative stress glutathione S-transferases (GST) and catalase (CAT) activities, and genotoxicity such as DNA adducts were evaluated, as well as general health conditions including condition index (CI), hepatosomatic index (HSI), and gonadosomatic index (GSI). PAH metabolite values were low and not significantly different when measured with the fixed-wavelength fluorescence screening method, while the gas chromatography–mass spectroscopy (GC-MS) method showed an apparent dose response in fish exposed to naphthalene. DNA adduct levels ≥0.16 × 10−8 relative adduct level (RAL) were detected. It should be noted that 0.16 × 10−8 RAL is considered the maximal acceptable background level for this species. The other biomarkers activities of catalase, GST, and EROD did not display a particular compound- or dose-related response. The GSI values were significantly lower in some chrysene- and in both naphthalene- and naphthalene diol-exposed groups compared to control.