Hans-Joachim Lehmler

Synthesis of hydroxylated PCB metabolites with the Suzuki-coupling

An improved synthesis of hydroxylated polychlorinated biphenyls (PCBs) which are structurally related to the major hydroxy PCB congeners identified in human plasma is described. The coupling of (chlorinated) aryl boronic acids with bromochloro anisoles using the standard conditions of the Suzuki coupling gave the desired hydroxylated PCB metabolites in good to excellent yields. The approach offers the advantage of high selectivity and good yields compared to conventional methods such as the Cadogan reaction and allows the use of less toxic starting materials.

Polychlorinated biphenyls as initiators in liver carcinogenesis: resistant hepatocyte model.

A modified Solt-Farber protocol was established to investigate the potential initiating activity of lower chlorinated polychlorinated biphenyl (PCB) congeners in rat liver. Two different studies were conducted in male Fisher 344 rats. PCBs investigated were PCB3, PCB12, PCB38, and PCB77 in study 1 and PCB15, PCB52, PCB77, and the combination of PCB52 and PCB77 in study 2. Rats were subjected to partial hepatectomy followed by a single dose of the suspected initiating agent, diethylnitrosamine, or vehicle. Two weeks later all groups received selection treatment consisting of three daily doses of 2-acetylaminofluorene (2-AAF) and then a single dose of carbon tetrachloride, followed by three additional daily treatments of 2-AAF via gavage. Rats were killed 2 weeks after the last treatment of 2-AAF, and the number and volume of gamma-glutamyltranspeptidase (GGT)-positive foci were determined. Among the PCBs tested, PCB3, PCB15, PCB52, and PCB77 significantly increased the number of GGT-positive foci per cm(3) of liver and per liver. Only PCB3 and PCB15 increased the volume fraction of GGT-positive foci. Histopathologic analysis of hematoxylin- and eosin-stained liver sections showed that rats with significantly increased GGT-positive foci also had extensive cellular alteration. This effect was not seen in nonselection groups. We conclude that, under the conditions and time courses of these experiments, several PCBs have initiating activity in male Fischer 344 rats.

Synthesis of polychlorinated biphenyls (PCBs) using the Suzuki-coupling

An improved synthesis of polychlorinated biphenyls (PCBs) utilizing a palladium-catalyzed cross-coupling reaction (Suzuki-coupling) is described. The coupling of (chlorinated) aryl boronic acids 1-3 with bromochlorobenzenes 4 using the standard conditions of the Suzuki-coupling gave the desired PCB congeners 5-7 in good to excellent yields. The self-coupling product of the aryl boronic acids is the major impurity of this reaction. 3,4,5-trichlorophenyl derivatives such as 10 can be synthesized by coupling of an aryl boronic acid with the corresponding bromochloroaniline 8. The approach offers the advantage of high selectivity and good yields compared to conventional methods such as the Cadogan reaction and allows the use of less toxic starting materials.

Behavior of partially fluorinated carboxylic acids at the air-water interface

Abstract Langmuir isotherms were recorded for 1-(perfluorobutyl)undecanoic acid (F 3 C(CF 2 ) 3 (CH 2 ) 10 CO 2 H), 1-(perfluorohexyl)undecanoic acid (F 3 C(CF 2 ) 5 (CH 2 ) 10 CO 2 H) and 1-(perfluorooctyl)undecanoic acid (F 3 C(CF 2 ) 7 (CH 2 ) 10 CO 2 H), their hydrocarbon analog, perfluorododecanoic and perfluorotetradecanoic acid after spreading onto hydrochloric acid (pH=1.9–2.0) at 32°C. All acids formed stable monolayers at the air–water interface. 1-(Perfluorobutyl)undecanoic acid shows some similarity to the compression isotherm of tetradecanoic acid while lacking the phase transition of pentadecanoic acid. The isotherm for 1-(perfluorohexyl)undecanoic acid shows a temperature-dependent phase transition similar to the liquid expanded-liquid condensed transition of pentadecanoic acid. The π-A isotherm of 1-(perfluorooctyl)undecanoic acid resembles the highly condensed monolayers of hepta- and nonadecanoic acid. Thus, the partially fluorinated acids seem to exhibit isotherm characteristics similar to hydrocarbon acids with shorter chain lengths. The three partially fluorinated acids have a higher limiting area compared to hydrocarbon and perfluorocarbon acids, which may be atributed to the strong dipole moment of the CF 2 CH 2  linkage. Within this series of partially fluorinated carboxylic acids, the limiting area decreases with chain lengthening and a higher degree of fluorination. The collapse pressures of the fluorinated acids are smaller compared to their respective hydrocarbon analog.

Chemical Stability of Esters of Nicotinic Acid Intended for Pulmonary Administration by Liquid Ventilation

AbstractPurpose. It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated. Methods. The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated. Results. Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4. Conclusions. The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.

2,4,4′‐trichlorobiphenyl increases STAT5 transcriptional activity

The promoting effects of polychlorinated biphenyls (PCBs) have been studied extensively in a variety of two‐stage carcinogenesis models. However, the molecular mechanisms responsible for the promotion effects of PCBs have not been elucidated. We measured the effect of PCBs on DNA‐binding proteins involved in cell proliferation and transformation. Male Sprague‐Dawley rats were injected intraperitoneally with mono‐, di‐, tri‐, tetra‐, or hexachlorobiphenyls (300 μmol/kg/d) each day for 4 d and killed 4 h after the last injection. To detect alterations in nuclear proteins that could explain the tumor‐promoter activity of PCBs, liver nuclear extracts were analyzed by electrophoretic mobility shift assays. Electrophoretic mobility shift assay analysis of signal transducers and activators of transcription (STAT)–binding activity to a consensus γ‐interferon–activated sequence (GAS) element was compared in liver nuclear extracts from treated rats. STAT‐binding activity was eightfold to tenfold higher in nuclear extracts from animals treated with 2,4,4′‐trichloro‐ (PCB 28) and 2,2′,4,4′,5,5′‐hexachlorobiphenyl (PCB 153). Analysis of the protein complex binding to the GAS element, with antibodies specific for STAT3, STAT5, and STAT6, indicated that the protein complex was made up of STAT5 and STAT6 proteins. HepG2 cells transiently transfected with a luciferase reporter gene construct containing many STAT5 binding sites were treated with PCB 28 and PCB 153. PCB 28 stimulated a greater than 25‐fold increase in luciferase activity at the highest concentration tested, 1.0 μg/mL. However, enhanced luciferase activity did not occur with PCB 153 treatment. 4‐Chlorobiphenyl (PCB 3), PCB 28, and PCB 153 treatment of Sprague‐Dawley rats resulted in a large increase in protein binding to a consensus activated protein‐1 (AP‐1) element. However, 3,4‐dichlorobiphenyl (PCB 12) and 3,3′,4,4′‐tetrachlorobiphenyl (PCB 77) treatments did not increase AP‐1 transcription activity. Further analysis of the proteins binding to the AP‐1 consensus sequence with antibodies specific for c‐fos, junD, and junB indicated that the protein composition consists of junD proteins. These data showed functional differences between noncoplanar and coplanar PCBs with respect to STAT activation and AP‐1–DNA binding.

2-(3,5-Di­chloro­phenyl)-1,4-benzo­quinone

In the title compound, C12H6Cl5O2, the dihedral angle between the two rings is 37°. This dihedral angle is different from the calculated dihedral angle in aqueous solution (48°), a likely cause being the influence of crystal packing.

A Novel Synthesis of Branched High-molecular-weight (C40 +) Long-chain Alkanes

Many biological and geochemical questions remain concerning the structures, functions, and properties of naturally occurring high-molecular-weight (C40 +) alkanes with various mid-chain alkylation patterns. Above C40, these alkanes are exceedingly difficult to separate and purify, and syntheses can be blocked by the low solubility of intermediates. To overcome these problems, a facile three-step synthesis employing the alkylation of 1,3-dithiane with a suitable α,ω-dibromoalkane was developed. Bisalkylation of the bis(dithianyl)alkane intermediate with the appropriate 1-bromoalkane and subsequent desulfurization with Raney nickel furnished the desired long-chain alkane. Long-chain alkanes modified at mid-chain and/or symmetrically near the chain termini (or unmodified, i.e., long-chain n-paraffins) are accessible by the selection of appropriate bromoalkanes. Nine mid-chain methylated (C38H78 to C53H108), one symmetrical terminal-chain dimethylated (C40H82), and four linear (C44H90 to C58H118) long-chain alkanes were synthesized by using this approach. High-temperature gas chromatography (HTGC) was found to have important advantages for evaluating the purity of the synthetic high-molecular-weight alkanes.