Publications by authors named "Marco Müller"

30 Publications

  • Page 1 of 1

Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres.

Nat Chem 2021 04 8;13(4):327-334. Epub 2021 Apr 8.

Department of Chemistry, University of Zurich, Zurich, Switzerland.

The asymmetric construction of all-carbon quaternary centres within acyclic settings represents a long-standing challenge for synthetic chemists. Alongside polar and radical methods, rearrangement reactions represent an attractive platform, but still broadly applicable methods are in high demand. Here we report an asymmetric, radical sulfinyl-Smiles rearrangement to access acyclic amides that bear an α-all-carbon quaternary centre. Our strategy uses enantioenriched N-arylsulfinyl acrylamides as acceptors for a variety of radicals produced in situ under mild photoredox conditions. The sulfinamido group not only directs the 1,4-migration of the aryl moiety onto the α-carbon of the amide, which thus governs its absolute configuration, but also functions as a traceless chiral auxiliary. The amides obtained in this multicomponent process are prevalent in pharmaceuticals, agrochemicals and bioactive natural products, and can be transformed into valuable chiral α,α-disubstituted acids, oxindoles as well as into β,β-disubstituted amines, highlighting the synthetic potential of this transformation.
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http://dx.doi.org/10.1038/s41557-021-00668-4DOI Listing
April 2021

Promoting Photocatalytic Hydrogen Evolution Activity of Graphitic Carbon Nitride with Hole-Transfer Agents.

ChemSusChem 2021 Jan 27;14(1):306-312. Epub 2020 Nov 27.

Metalorganics and Inorganic Materials, Department of Chemistry, Technische Universität Berlin, Straße des 17 Juni 135, Sekr. C2, 10623, Berlin, Germany.

Visible light-driven photocatalytic reduction of protons to H is considered a promising way of solar-to-chemical energy conversion. Effective transfer of the photogenerated electrons and holes to the surface of the photocatalyst by minimizing their recombination is essential for achieving a high photocatalytic activity. In general, a sacrificial electron donor is used as a hole scavenger to remove photogenerated holes from the valence band for the continuation of the photocatalytic hydrogen (H ) evolution process. Here, for the first time, the hole-transfer dynamics from Pt-loaded sol-gel-prepared graphitic carbon nitride (Pt-sg-CN) photocatalyst were investigated using different adsorbed hole acceptors along with a sacrificial agent (ascorbic acid). A significant increment (4.84 times) in H production was achieved by employing phenothiazine (PTZ) as the hole acceptor with continuous H production for 3 days. A detailed charge-transfer dynamic of the photocatalytic process in the presence of the hole acceptors was examined by time-resolved photoluminescence and in situ electron paramagnetic resonance studies.
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http://dx.doi.org/10.1002/cssc.202002500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839742PMC
January 2021

α-Tocomonoenol Is Bioavailable in Mice and May Partly Be Regulated by the Function of the Hepatic α‑Tocopherol Transfer Protein.

Molecules 2020 Oct 19;25(20). Epub 2020 Oct 19.

Department of Food Biofunctionality, Institute of Nutritional Sciences, University of Hohenheim, Garbenstr. 28, D-70599 Stuttgart, Germany.

Tocomonoenols are vitamin E derivatives present in foods with a single double bond at carbon 11' in the sidechain. The α-tocopherol transfer protein (TTP) is required for the maintenance of normal α-tocopherol (αT) concentrations. Its role in the tissue distribution of α-11'-tocomonoenol (αT) is unknown. We investigated the tissue distribution of αT and αT in wild-type (TTP) and TTP knockout (TTP) mice fed diets with either αT or αT for two weeks. αT was only found in blood, not tissues. αT concentrations in TTP mice were in the order of adipose tissue > brain > heart > spleen > lungs > kidneys > small intestine > liver. Loss of TTP function depleted αT in all tissues. αT, contrary to αT, was still present in the blood of TTP mice (16% of αT in TTP). Autoclaving and storage at room temperature reduced αT and αT in experimental diets. In conclusion, αT is bioavailable, reaches the blood in mice, and may not entirely depend on TTP function for secretion into the systemic circulation. However, due to instability of the test compounds in the experimental diets, further in vivo experiments are required to clarify the role of TTP in αT secretion. Future research should consider compound stability during autoclaving of rodent feed.
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http://dx.doi.org/10.3390/molecules25204803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588010PMC
October 2020

Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature.

Toxics 2020 Jun 3;8(2). Epub 2020 Jun 3.

Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weissenburger Straße 3, 76187 Karlsruhe, Germany.

Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.
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http://dx.doi.org/10.3390/toxics8020041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357058PMC
June 2020

Identification of two α-tocodienol isomers in palm oil after countercurrent chromatographic enrichment.

Anal Bioanal Chem 2020 Jan 19;412(3):795-802. Epub 2019 Dec 19.

Institute of Food Chemistry, Department of Food Chemistry (170b), University of Hohenheim, Garbenstr. 28, 70593, Stuttgart, Germany.

Countercurrent chromatography (CCC) was used for the enrichment of α-tocodienol (α-T), a rare vitamin E-related minor compound previously tentatively detected in palm oil. Hitherto, only one isomer has been mentioned to occur at traces in palm oil. However, CCC fractionation followed by GC/MS measurements of all fractions resulted in the detection of two α-T isomers in five different palm oil vitamin E dietary supplement capsules. Five repetitive CCC separations of ~ 1 g sample and additional purification steps by column chromatography provided ~ 2 mg of two equally abundant α-T isomers with a purity of ~ 85%. The positions of the double bonds in the alkyl side chain could be assigned by means of two characteristic chemical shifts in the H NMR spectrum. Accordingly, the structures of the α-T isomers were 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridec-3,11-dienyl)chroman-6-ol (double bonds in 3',11'-position) and 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridec-7,11-dienyl)chroman-6-ol (double bonds in 7',11'-position). Natural occurrence of both isomers was proven by GC/MS screening of crude palm oil after saponification and CCC separation. Moreover, GC/MS analysis allowed the tentative assignment of γ-tocomonoenol (γ-T) and β-tocomonoenol (β-T) as trace compounds in palm oil.
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http://dx.doi.org/10.1007/s00216-019-02303-1DOI Listing
January 2020

Direct H NMR Quantitation of Valuable Furan Fatty Acids in Fish Oils and Fish Oil Fractions.

J Agric Food Chem 2019 Oct 14;67(42):11788-11795. Epub 2019 Oct 14.

Institute of Food Chemistry, Department of Food Chemistry (170b) , University of Hohenheim , D-70593 Stuttgart , Germany.

Furan fatty acids (FuFAs) are a class of naturally occurring minor fatty acids with fish as the richest food source. Typically, FuFA analysis is cumbersome and involves several steps. We developed a quantitative H NMR method (qNMR) in which fish oil samples were directly measured after dilution with CDCl stabilized with silver (which was essential to prevent formation of radicals) and addition of an internal standard. The singlet at δ = 1.89 ppm was suitable for quantitation of monomethyl FuFAs, whereas the signal at δ = 1.83 ppm was suitable to quantitate dimethyl FuFAs. Using standard NMR tubes with 650 μL solvent, the limit of quantitation was 0.5 μg (dimethyl FuFAs) and 1.0 μg (monomethyl FuFAs). Applied to three fish oil and two enriched fish oil samples (sample weight, 10 mg), the final qNMR method resulted in similar total FuFA contents as determined in parallel by gas chromatography coupled to mass spectrometry.
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http://dx.doi.org/10.1021/acs.jafc.9b04711DOI Listing
October 2019

Development of equivalent chain length (ECL) rules for lipid compounds.

J Chromatogr A 2019 Aug 17;1599:187-195. Epub 2019 Apr 17.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70593 Stuttgart, Germany.

Lipid compounds (fatty acids, tocochromanols, phytosterols) are difficult to separate by countercurrent chromatography (CCC) due to the existence of many similar structures and the limited availability of suitable biphasic solvent systems. Here we show that for these compound classes the success of a CCC separation can be directly derived from the chemical structures without the necessity of experimental determinations of K values. In most cases, lipid compounds differ in the total carbon number and the number of double bonds. For each structure the so-called equivalent chain length (ECL) can be calculated by subtracting a distinct value for each double bond from the total carbon number. Empirically, we verified that in the case of unbranched fatty acids (determined as methyl esters) one double bond corresponds with two carbons. Evaluation of CCC data from seventeen phytosterols in five plant oils and nine tocochromanol standards showed that one double bond was equal with one carbon for both lipid classes. Most compounds with different ECL can be separated by CCC but not those with the same ECL. In these cases, the selection of a suitable source for isolation of a particular lipid compound becomes very important. Knowledge of the impact of double bonds may also be a helpful tool for other substance classes.
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http://dx.doi.org/10.1016/j.chroma.2019.04.042DOI Listing
August 2019

Improving the resolution of overlapping peaks by heartcut two-dimensional countercurrent chromatography with the same solvent system in both dimensions.

J Chromatogr A 2019 Jul 13;1596:142-151. Epub 2019 Mar 13.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70593 Stuttgart, Germany. Electronic address:

The countercurrent chromatographic (CCC) isolation of structurally related compounds with high chemical purity can be challenging, especially in the field of lipids, were the range of biphasic solvent systems is limited. In the past, special elution modes like recycling CCC or re-injection of pooled fractions into a subsequent CCC (off-line re-injection CCC) were applied successfully to improve the separation of interfering compounds. However, isolation of minor compounds is often hampered by overlapping major compounds in natural samples. In this study we used heartcut two-dimensional CCC (2D CCC) to transfer the analyte completely to the next dimension while the interfering compound was partly removed. This procedure not only reduced the amount of the interfering major compound but also its peak width by up to 20% in the second dimension despite the longer elution time. Since the same solvent system and coil dimensions were used in the second dimension, this positive effect was attributed to the "transfer volume" which can be compared to an injection volume into the second dimension. As a consequence, improved peak resolution was generally observed for peaks which were partly transferred to the next dimension. This unexpected beneficial effect of 2D CCC on peak resolution was demonstrated by means of two examples in comparison with CCC in recycling and off-line re-injection mode. Applying the same CCC conditions, heartcut 2D CCC yielded >14 mg of the pentacyclic triterpenol lupeol, isolated from the unsaponifiable matter of shea butter, while recycling CCC and one-dimensional CCC only yielded ∼5 and ∼1 mg, respectively. Moreover, the resolution of three different ergosterol derivates (ergosta-5,7-dienol, ergosta-7,22-dienol and ergost-7-enol) which were separated from the very abundant ergosterol in the unsaponifiable matter of freeze-dried button mushrooms could be improved with heartcut 2D CCC compared with off-line re-injection CCC.
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http://dx.doi.org/10.1016/j.chroma.2019.03.012DOI Listing
July 2019

A phantom study to create synthetic CT from orthogonal twodimensional cine MRI and evaluate the effect of irregular breathing.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:4162-4165

An exciting innovation in radiotherapy is the use of real-time MRI for treatment adaptation. This study proposes an in-silico framework for the generation of 3D synthetic CT (sCT) from orthogonal interleaved 2D cine MRI data to overcome the lack of electron density information in MR images. The method uses pre-treatment data to build a patient breathing motion model. This model is then driven by surrogates extracted from cine MR images during the treatment. The effect of irregular breathing on the motion model is also evaluated by simulating different motion components related to uncorrelated diaphragm, chest and tumor motion. 3D sCT were successfully created for each of the 512 cine MRI pairs in the digital phantom study. The analysis showed that the diaphragm position was a good surrogate to rescale the 3D breathing motion for the current regular breathing phase. However, respiratory and tumor motion were correlated in only 59% of the phases, resulting in tumor position uncertainties of up to 3mm. The inclusion of additional chest and tumor motion information improved the accuracy for irregular changes in breathing pattern and enhanced the tumor position uncertainties to less than 1mm. This study successfully demonstrated a proof-ofprinciple for a digital phantom dataset based on patient parameters, providing a way to create real-time 3D electron density volumes and enhancing the need to account for irregular breathing pattern.
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http://dx.doi.org/10.1109/EMBC.2018.8513236DOI Listing
July 2018

Thorough study of persistent organic pollutants and halogenated natural products in sperm whale blubber through preparative sample cleanup followed by fractionation with countercurrent chromatography.

J Chromatogr A 2018 Aug 19;1565:114-123. Epub 2018 Jun 19.

University of Hohenheim, Institute of Food Chemistry (170b), Garbenstraße 28, D-70599 Stuttgart, Germany.

Marine mammals are top predators of the marine food chain and thus known to bioaccumulate high concentrations of polyhalogenated compounds. Yet, details of the organohalogen pattern are largely unknown. For this reason, we isolated the polyhalogenated compounds from 750 g blubber of a sperm whale (Physeter catodon), which deceased at the German North Sea coast in January 2016. The sample matrix was decomposed by sulfuric acid treatment and the polyhalogenated compounds were then fractionated by countercurrent chromatography (CCC). Seventy-three CCC fractions were taken and analyzed by gas chromatography with electron capture negative ion mass spectrometry (GC/ECNI-MS). The bulk of the polyhalogenated compounds in the sample originated from classic persistent organic pollutants (POPs). Altogether 90 polychlorinated biphenyl (PCB) congeners were detected in the sample including all possible octa- to decachloro congeners except one. The sample also featured 105 toxaphene congeners including 30 chlorobornenes (contribution ∼14% of the total toxaphene content) which were only detected after the CCC fractionation. In addition, several chlordane and mirex related compounds were detected which were never or very scarcely described before in biota. Classic POPs (PCBs, DDT, toxaphene, chlordane, mirex) were predominant, while new emerging contaminants were scarcely detected. The sample featured several halogenated natural products (HNPs) some of which were less stable and destroyed during the sample cleanup involving treatment with sulfuric acid. Sample fractionation by means of CCC was crucial for the detection and assignment of many of the uncommon polyhalogenated compounds.
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http://dx.doi.org/10.1016/j.chroma.2018.06.037DOI Listing
August 2018

Multiple injection mode with or without repeated sample injections: Strategies to enhance productivity in countercurrent chromatography.

J Chromatogr A 2018 Jun 1;1556:88-96. Epub 2018 May 1.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70593 Stuttgart, Germany. Electronic address:

Countercurrent chromatography (CCC) is an all liquid based separation technique typically used for the isolation and purification of natural compounds. The simplicity of the method makes it easy to scale up CCC separations from analytical to preparative and even industrial scale. However, scale-up of CCC separations requires two different instruments with varying coil dimensions. Here we developed two variants of the CCC multiple injection mode as an alternative to increase the throughput and enhance productivity of a CCC separation when using only one instrument. The concept is based on the parallel injection of samples at different points in the CCC column system and the simultaneous separation using one pump only. The wiring of the CCC setup was modified by the insertion of a 6-port selection valve, multiple T-pieces and sample loops. Furthermore, the introduction of storage sample loops enabled the CCC system to be used with repeated injection cycles. Setup and advantages of both multiple injection modes were shown by the isolation of the furan fatty acid 11-(3,4-dimethyl-5-pentylfuran-2-yl)-undecanoic acid (11D5-EE) from an ethyl ester oil rich in 4,7,10,13,16,19-docosahexaenoic acid (DHA-EE). 11D5-EE was enriched in one step from 1.9% to 99% purity. The solvent consumption per isolated amount of analyte could be reduced by ∼40% compared to increased throughput CCC and by ∼5% in the repeated multiple injection mode which also facilitated the isolation of the major compound (DHA-EE) in the sample.
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http://dx.doi.org/10.1016/j.chroma.2018.04.069DOI Listing
June 2018

Countercurrent chromatographic isolation and purification of 11'-α-tocomonoenol from the vitamin E extract of palm oil.

Food Chem 2018 Aug 26;256:327-332. Epub 2018 Feb 26.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70599 Stuttgart, Germany. Electronic address:

A new vitamin E homologue, α-tocomonoenol was detected in palm oil, but was not isolated in large amounts and with high purity so far. Here we present an easy and fast method to isolate α-tocomonoenol from vitamin E rich nutrient capsules with countercurrent chromatography (CCC). With the solvent system n-hexane - benzotrifluoride - acetonitrile (10:3.5:6.5, v/v/v) about 30 mg α-tocomonoenol with a purity of 75% could be enriched in one step from 1 g crude sample. Column chromatography with 20% deactivated silica gel and n-hexane - ethyl acetate (95:5, v/v) was performed to gain 5.6 mg α-tocomonoenol with a purity of 99.5% according to GC/MS. Structural verification by H NMR spectroscopy verified that the double bond was located in 11'-position (11'-α-tocomonoenol). The trace impurity detected in the isolate was identified to be 12'-α-tocomonoenol, a compound previously detected in marine samples.
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http://dx.doi.org/10.1016/j.foodchem.2018.02.133DOI Listing
August 2018

Prospective feasibility analysis of a novel off-line approach for MR-guided radiotherapy.

Strahlenther Onkol 2018 05 18;194(5):425-434. Epub 2018 Jan 18.

Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Background: The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies.

Patients And Methods: 20 patients with pelvic malignancies were included in this prospective feasibility analysis. Patients underwent daily MRI in treatment position prior to radiotherapy at the German Cancer Research Center. Positional inaccuracies, time and patient compliance were assessed for the application of off-line MRgRT.

Results: In 78% of applied radiation fractions, MR imaging for position verification could be performed without problems. Additionally, treatment-related side effects and reduced patient compliance were only responsible for omission of MRI in 9% of radiation fractions. The study workflow took a median time of 61 min (range 47-99 min); duration for radiotherapy alone was 13 min (range 7-26 min). Patient positioning, MR imaging and CT imaging including patient repositioning and the shuttle transfer required median times of 10 min (range 7-14 min), 26 min (range 15-60 min), 5 min (range 3-8 min) and 8 min (range 2-36 min), respectively. To assess feasibility of shuttle-based MRgRT, the reference point coordinates for the x, y and z axis were determined for the MR images and CT obtained prior to the first treatment fraction and correlated with the coordinates of the planning CT. In our dataset, the median positional difference between MR imaging and CT-based imaging based on fiducial matching between MR and CT imaging was equal to or less than 2 mm in all spatial directions. The limited space in the MR scanner influenced patient selection, as the bore of the scanner had to accommodate the immobilization device and the constructed stereotactic frame. Therefore, obese, extremely muscular or very tall patients could not be included in this trial in addition to patients for whom exposure to MRI was generally judged inappropriate.

Conclusion: This trial demonstrated for the first time the feasibility and patient compliance of a shuttle-based off-line approach to MRgRT of pelvic malignancies.
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http://dx.doi.org/10.1007/s00066-017-1258-yDOI Listing
May 2018

Procedures for the GMP-Compliant Production and Quality Control of [F]PSMA-1007: A Next Generation Radiofluorinated Tracer for the Detection of Prostate Cancer.

Pharmaceuticals (Basel) 2017 Sep 27;10(4). Epub 2017 Sep 27.

German Cancer Research Center (DKFZ), Division of Radiopharmaceutical Chemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [F]DCFPyL and [F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.
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http://dx.doi.org/10.3390/ph10040077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748634PMC
September 2017

Concentrations, Stability, and Isolation of the Furan Fatty Acid 9-(3-Methyl-5-pentylfuran-2-yl)-nonanoic Acid from Disposable Latex Gloves.

J Agric Food Chem 2017 Sep 5;65(36):7919-7925. Epub 2017 Sep 5.

Department of Food Chemistry (170b), Institute of Food Chemistry, University of Hohenheim , Garbenstraße 28, D-70593 Stuttgart, Germany.

Because of their antioxidant properties, furan fatty acids (furan-FAs) are valuable minor compounds with a widespread occurrence in all living matter. Unfortunately, pure standards are not readily available, because they usually contribute only 1% to the lipid fraction. A known exception of this is the milky fluid of Hevea brasiliensis, commonly known as latex, in which the furan-FA 9-(3-methyl-5-pentylfuran-2-yl)-nonanoic acid (9M5) contributes about 90% to the triacylglycerides. In this study, we investigated the content of 9M5 in 30 different disposable latex gloves, which ranged from 0.7 to 8.2 mg/g of glove. The light degradability of 9M5 in latex gloves was investigated, and different amounts of 9M5 in disposable latex gloves were attributed to varying exposure time to light. Additionally, over 100 mg of the methyl or ethyl ester of 9M5 (purity of >98%) could be extracted from disposable latex gloves, employing cold extraction and silver ion chromatography. With this method, standards for the quantitation of furan-FAs are obtained easily and rapidly in all laboratories.
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http://dx.doi.org/10.1021/acs.jafc.7b02444DOI Listing
September 2017

The use of countercurrent chromatography in the separation of nonpolar lipid compounds.

J Chromatogr A 2017 Jun 15;1501:51-60. Epub 2017 Apr 15.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70593 Stuttgart, Germany.

Isolation of lipophilic compounds by countercurrent chromatography (CCC) is a challenge because biphasic solvent systems in which these compounds distribute evenly are difficult to obtain. In this article we present novel applications of lipid compound isolation from natural sources. Conjugated linolenic acids (CLnAs, log K ∼7) were isolated from pomegranate oil using a solvent system consisting of n-heptane/methanol/water 100:91:9 (v/v/v). The CLnA fraction was free of other fatty acids but consisted of different isomers which were not resolved from each other. In the less polar range (log K ∼12), three tocotrienols (α-, γ- and δ-tocotrienol) were isolated from a vitamin E capsule produced from palm oil by using the solvent system n-hexane/acetonitrile/benzotrifluoride (BTF) at a ratio of 10:6.5:3.5 (v/v/v). Between 36 and 65mg of each of the three tocotrienols were obtained in one injection with purities >97%. Advantages and disadvantages of the "BTF system" are discussed by comparing the phase composition with the simple n-hexane/acetonitrile system and by the fractionation of phytosterols (log K ∼9.5) from rapeseed oil.
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http://dx.doi.org/10.1016/j.chroma.2017.04.035DOI Listing
June 2017

Development of solvent systems with room temperature ionic liquids for the countercurrent chromatographic separation of very nonpolar lipid compounds.

J Chromatogr A 2017 Mar 27;1488:68-76. Epub 2017 Jan 27.

University of Hohenheim, Institute of Food Chemistry, Department of Food Chemistry (170b), D-70593 Stuttgart, Germany. Electronic address:

Solvent systems are not readily available for the separation of very nonpolar compounds by countercurrent chromatography (CCC). In this study we therefore evaluated the suitability of room temperature ionic liquids (IL) in organic solvents for the CCC separation of the extremely nonpolar lipid compounds tripalmitin (PPP) and cholesteryl stearate (CS). The four IL tested were [Cmim][OTf], [Cmim][NTf], [P66614][NTf], and [P66614][Cl]. Search for a CCC-suited solvent system started with solubility studies with fourteen organic solvents. Following this, combinations were made with one organic solvent miscible and one organic solvent immiscible with IL (147 combinations). Twenty-four initially monophasic mixtures of two organic solvents became biphasic by adding IL. Several unexpected results could be observed. For instance, n-hexane and n-heptane became biphasic with [P66614][Cl]. Further nine systems became biphasic although the IL was not miscible in any of the two components. These 33 solvent systems were investigated with regard to phase ratio, settling time, share of IL in the upper phase and last not least the K values of PPP and CS, which were 8.1 and 7.7 respectively. The most promising system, n-heptane/chloroform/[Cmim][OTf] (3:3:1, v/v/v) allowed a partial separation of PPP and CS by CCC which was not achieved beforehand.
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http://dx.doi.org/10.1016/j.chroma.2017.01.074DOI Listing
March 2017

Accelerated separation of GC-amenable lipid classes in plant oils by countercurrent chromatography in the co-current mode.

Anal Bioanal Chem 2015 Dec 5;407(30):9019-28. Epub 2015 Oct 5.

Institute of Food Chemistry (170b), University of Hohenheim, Garbenstraße 28, 70599, Stuttgart, Germany.

Triacylglycerols represent the major part (>90%) in most plant oils and have to be eliminated, when the minor compounds such as phytosterols or tocopherols should be analyzed. Here, we used an all liquid-liquid chromatographic technique, countercurrent chromatography (CCC), to fractionate the minor lipids before gas chromatography (GC) analysis. To cover the wide range of polarity of the minor compounds, we used the co-current mode, in which both mobile and stationary phase are pumped through the system. This allowed to elute substances which partitioned almost exclusively in the stationary phase within 90 min. After testing with standard compounds, the method was applied to the separation of sesame oil and sunflower oil samples. The abundant triacylglycerols could be effectively separated from tocopherols, phytosterols, diacylglycerols, and free fatty acids in the samples, and these compounds could be analyzed (after trimethylsilylation) by GC coupled with mass spectrometry. After the enrichment caused by the CCC fractionation, we were also able to identify the tocopherol derivative α-tocomonoenol, which had not been described in sunflower oil before. Also, separation of sesame oil yielded a mixture of the polar compounds sesamin and sesamolin without further impurities.
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http://dx.doi.org/10.1007/s00216-015-9068-5DOI Listing
December 2015

Development and Successful Validation of Simple and Fast TLC Spot Tests for Determination of Kryptofix® 2.2.2 and Tetrabutylammonium in 18F-Labeled Radiopharmaceuticals.

Pharmaceuticals (Basel) 2014 May 14;7(5):621-33. Epub 2014 May 14.

Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 15, Tübingen D-72076, Germany.

Kryptofix® 2.2.2 (Kry) or tetrabutylammonium (TBA) are commonly used as phase transfer catalysts in 18F-radiopharmaceutical productions for positron emission tomography (PET). Due to their toxicity, quality control has to be performed before administration of the tracer to assure that limit concentration of residual reagent is not reached. Here, we describe the successful development and pharmaceutical validation (for specificity, accuracy and detection limit) of a simplified color spot test on TLC plates. We were able to prove its applicability as a general, time and resources saving, easy to handle and reliable method in daily routine analyzing 18F-tracer formulations for Kry (in [18F]FDG or [18F]FECh) or TBA contaminations (in [18F]FLT) with special regard to complex matrix compositions.
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http://dx.doi.org/10.3390/ph7050621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035771PMC
May 2014

Influence of different chelators on the radiochemical properties of a 68-Gallium labelled bombesin analogue.

Nucl Med Biol 2014 Jan 31;41(1):24-35. Epub 2013 Oct 31.

Nuclear Medicine Unit, Oncology and Advanced Technologies Department, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. Electronic address:

Unlabelled: The radiolabelled bombesin analogue AMBA shows high potential for diagnosis and treatment of prostate and breast cancer, but the influence of different chelators, which differ in terms of radiochemical reactivity and stability, have not been explored so far. In order to find the best suitable chelator for labelling of AMBA, we synthesized AMBA analogues linked to the most commonly used chelators DOTA, NOTA and NODAGA and compared their reactivity and stability after labelling with 68-Gallium.

Methods: For the synthesis of DO3A-, NO2A- and NODAGA-AMBA, a solid-phase synthesis approach was used. The influence of concentration, pH and temperature on the radiolabelling was analysed. The in vitro stability of all complexes in saline, human serum, human whole blood and against transchelation and transmetallation was analysed.

Results: The peptides were synthesised in high yield and purity. Purity and identity of products and impurities were confirmed using UHPLC coupled to ESI-MS. Radiolabelling of these peptides was optimal at elevated temperature, although room temperature labelling was reported previously for NOTA and NODAGA chelators. The highest reactivity was observed for NODAGA-AMBA. On preparation of NO2A-AMBA, the formation of a by-product was detected with HPLC. More detailed analysis revealed the formation of an isomer with the same mass to charge ratio which led to the conclusion that a coordination isomer was formed. All complexes showed high stability in saline, human serum or when challenged with DTPA, transferrin and varying metals (Fe(3+), Cu(2+), Zn(2+)). Conversely, the stability in human blood was low, and varying metabolites were detected and identified by ESI-MS.

Conclusion: All three precursors are available in high yields suitable for routine production. NODAGA-AMBA showed the most favoured features when labelled with 68-gallium, but a further comparison in vivo should be performed in order to confirm the superior features found in vitro.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.08.010DOI Listing
January 2014

Some chemistry of tris(pyrazolyl)methylthiolate derivatives.

Acta Chim Slov 2013 ;60(3):569-76

An efficient synthetic method for the preparation of TAS tris(pyrazolyl)methylthiolate (3) is reported. Nucleophilic exchange reactions with 3 gave (pyr)C(=S)SC(pyr)3 (4) and MeSC(pyr)3 (5). 5 acts as scorpionate ligand in [MeSC(pyr)3Cr(CO)3] (6), from the decomposition of TDAE2+ [SC(pyr)3Mo(CO)3-]2 by SO2FCl TDAE2+[O=MoF4-F-Mo(=O)Cl4]2- (8) was isolated. The X-ray structures of 3-6 and 8 are discussed.
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December 2013

Cationic eluate pretreatment for automated synthesis of [⁶⁸Ga]CPCR4.2.

Nucl Med Biol 2014 Jan 9;41(1):84-9. Epub 2013 Oct 9.

ABX advanced biochemical compounds, Heinrich-Glaeser-Str. 10-14, 01454 Radeberg, Germany. Electronic address:

Fostered by the clinical success of sst-ligands, the development and evaluation of (68)Ga-labeled peptides have become a very active field in radiopharmaceutical chemistry. Consequently, various new peptide tracers have been developed, e.g. [(68)Ga]CPCR4.2 for in vivo imaging of solid and haematological tumors or [(68)Ga]TRAP(RGD)₃ for imaging of α(v)β₃ integrin expression. As a consequence of different matrices (TiO₂, SnO₂, polymers) exploited in commercial (68)Ge/(68)Ga-generators, HCl of different concentrations (0.05...1.0 M) is used to obtain (68)Ga as starting material for automated syntheses. We have developed a purification method which reduces the eluate volume and adjusts the HCl concentration. The method may potentially allow standardization of the eluate composition of different commercial generators prior to labeling. Recently, a cationic purification process has been reported which allows the pre-fixation of (68)Ga on a Varian SCX cation exchange cartridge and subsequent elution of (68)Ga with acidified NaCl solutions. As part of the development of ready-to-use cassettes for the automated production of (68)Ga-CPCR4.2 using a SCINTOMICS GRP module and an iThemba Labs generator that is eluted with 0.6...1.0 M HCl, we tested and compared the (68)Ga-trapping efficiency of various commercial available cation exchange cartridges, the efficiency of subsequent (68)Ga-elution from these cartridges by means of various protocols and the influence of these variations on the labeling efficiency of [(68)Ga]CPCR4.2, [(68)Ga]TRAP(RGD)₃ and [(68)Ga]DOTATATE/[(68)Ga]DOTANOC. Finally, we transferred the optimized method to the automated, cassette based synthesis of [(68)Ga]CPCR4.2 and the aforementioned peptides. From seven tested cation exchange cartridges, Chromafix PS-H(+) gave the best extraction results (>95%). Moreover, we observed that acidified solutions of 5 M NaCl or 2.5 M CaCl₂ can be used for efficient cartridge elution. Using a disposable cGMP-compliant cassette system, we obtained [(68)Ga]CPCR4.2 in 80% decay-corrected yield and >99% purity. These data were confirmed by the production of [(68)Ga]DOTATATE, [(68)Ga]DOTANOC and [(68)Ga]TRAP(RGD)3 on the otherwise identical cassette system.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.09.002DOI Listing
January 2014

3D-QSAR based on quantum-chemical molecular fields: toward an improved description of halogen interactions.

J Chem Inf Model 2012 Sep 6;52(9):2441-53. Epub 2012 Sep 6.

Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Structure, Design and Informatics, Building G 878, 65926 Frankfurt am Main, Germany.

Current 3D-QSAR methods such as CoMFA or CoMSIA make use of classical force-field approaches for calculating molecular fields. Thus, they can not adequately account for noncovalent interactions involving halogen atoms like halogen bonds or halogen-π interactions. These deficiencies in the underlying force fields result from the lack of treatment of the anisotropy of the electron density distribution of those atoms, known as the "σ-hole", although recent developments have begun to take specific interactions such as halogen bonding into account. We have now replaced classical force field derived molecular fields by local properties such as the local ionization energy, local electron affinity, or local polarizability, calculated using quantum-mechanical (QM) techniques that do not suffer from the above limitation for 3D-QSAR. We first investigate the characteristics of QM-based local property fields to show that they are suitable for statistical analyses after suitable pretreatment. We then analyze these property fields with partial least-squares (PLS) regression to predict biological affinities of two data sets comprising factor Xa and GABA-A/benzodiazepine receptor ligands. While the resulting models perform equally well or even slightly better in terms of consistency and predictivity than the classical CoMFA fields, the most important aspect of these augmented field-types is that the chemical interpretation of resulting QM-based property field models reveals unique SAR trends driven by electrostatic and polarizability effects, which cannot be extracted directly from CoMFA electrostatic maps. Within the factor Xa set, the interaction of chlorine and bromine atoms with a tyrosine side chain in the protease S1 pocket are correctly predicted. Within the GABA-A/benzodiazepine ligand data set, PLS models of high predictivity resulted for our QM-based property fields, providing novel insights into key features of the SAR for two receptor subtypes and cross-receptor selectivity of the ligands. The detailed interpretation of regression models derived using improved QM-derived property fields thus provides a significant advantage by revealing chemically meaningful correlations with biological activity and helps in understanding novel structure-activity relationship features. This will allow such knowledge to be used to design novel molecules on the basis of interactions additional to steric and hydrogen-bonding features.
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http://dx.doi.org/10.1021/ci300253zDOI Listing
September 2012

Learning invariant face recognition from examples.

Neural Netw 2013 May 23;41:137-46. Epub 2012 Jul 23.

Institut für Neuroinformatik, Ruhr-Universität, D-44780 Bochum, Germany.

Autonomous learning is demonstrated by living beings that learn visual invariances during their visual experience. Standard neural network models do not show this sort of learning. On the example of face recognition in different situations we propose a learning process that separates learning of the invariance proper from learning new instances of individuals. The invariance is learned by a set of examples called model, which contains instances of all situations. New instances are compared with these on the basis of rank lists, which allow generalization across situations. The result is also implemented as a spike-time-based neural network, which is shown to be robust against disturbances. The learning capability is demonstrated by recognition experiments on a set of standard face databases.
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http://dx.doi.org/10.1016/j.neunet.2012.07.006DOI Listing
May 2013

Coaxial waveguide MRI.

Magn Reson Med 2012 Apr 21;67(4):1173-82. Epub 2011 Oct 21.

German Cancer Research Center, Heidelberg, Germany.

As ultrahigh-field MR imaging systems suffer from the standing wave problems of conventional coil designs, the use of antenna systems that generate travelling waves was suggested. As a modification to the original approach, we propose the use of a coaxial waveguide configuration with interrupted inner conductor. This concept can focus the radiofrequency energy to the desired imaging region in the human body and can operate at different Larmor frequencies without hardware modifications, as it is not limited by a lower cut-off frequency. We assessed the potential of the method with a hardware prototype setup that was loaded with a tissue equivalent phantom and operated with imaging areas of different size. Signal and flip angle distributions within the phantom were analyzed, and imaging at different Larmor frequencies was performed. Results were compared to a finite difference time domain simulation of the setup that additionally provides information on the spatial distribution of the specific absorption rate load. Furthermore, simulation results with a human model (virtual family) are presented. It was found that the proposed method can be used for MRI at multiple frequencies, achieving transmission efficiencies similar to other travelling wave approaches but still suffers from several limitations due to the used mode of wave propagation.
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http://dx.doi.org/10.1002/mrm.23069DOI Listing
April 2012

Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation.

J Med Chem 2010 Dec 17;53(24):8679-87. Epub 2010 Nov 17.

Sanofi-Aventis Deutschland GmbH, R&D, Diabetes Division, Industriepark Hoechst, Building G 878, D-65926 Frankfurt am Main, Germany.

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat utilization and their inhibition is considered to improve aspects of the metabolic syndrome. To identify pharmacological inhibitors of ACC1/2, a high throughput screen was performed which resulted in the identification of the lead compound 3 ( Gargazanli , G. ; Lardenois , P. ; Frost , J. ; George , P. Patent WO9855474 A1, 1998 ) as a moderate selective ACC2 inhibitor. Optimization of 3 led to 4m ( Zoller , G. ; Schmoll , D. ; Mueller , M. ; Haschke , G. ; Focken , I. Patent WO2010003624 A2, 2010 ) as a submicromolar dual ACC1/2 inhibitor of the rat and human isoforms. 4m possessed favorable pharmacokinetic parameters. This compound stimulated fat oxidation in vivo and reduced plasma triglyceride levels in a rodent model after subchronic administration. 4m is a suitable tool compound for the elucidation of the pharmacological potential of ACC1/2 inhibition.
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http://dx.doi.org/10.1021/jm101179eDOI Listing
December 2010

Inhomogeneous feed gas processing in industrial ozone generation.

Water Sci Technol 2008 ;58(11):2077-82

Degremont Technologies Ltd, Stettbachstrasse 1, 8600, Dübendorf, Switzerland.

The synthesis of ozone by means of dielectric barrier discharge (DBD) is extensively used in industry. Ozone generators available on the market differ in ozone production capacities, electrode arrangements and working parameters, but operate with a uniformly distributed filamentary discharge plasma pattern.In the presented work the benefits of inhomogeneous feed gas processing are explored. Causality between power induction, production efficiency and working parameters are investigated. Different electrode arrangements, evenly distributed within a given space parameter, were designed, simulated, manufactured and tested on a representative scale. A finite element model was utilized to simulate an inhomogeneous power induction pattern along the ozone generator tube. The simulation yielded the local power density, the local gas temperature gradient and the relative DBD packing density.Results show that the degree of filamentation turns out to be decisive, indicating a new potential by means of plasma tailoring. An arrangement with a pronounced power induction at the inlet of the ozone generator revealed several advantages over homogeneous plasma processing arrangements, for which an increase in robustness and a reduction in electrical power consumption are achieved.
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http://dx.doi.org/10.2166/wst.2008.760DOI Listing
March 2009

Age-dependent effects of severe traumatic brain injury on cerebral dopaminergic activity in newborn and juvenile pigs.

J Neurotrauma 2004 Aug;21(8):1076-89

Department of Neurosurgery, Friedrich Schiller University Jena, Germany.

There is evidence that the dopaminergic system is sensitive to traumatic brain injury (TBI). However, the age-dependency of this sensitivity has not been studied together with brain oxidative metabolism. We postulate that the acute effects of severe TBI on brain dopamine turnover are age-dependent. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with Positron-Emission-Tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of 11 newborn piglets (7-10 days old) and nine juvenile pigs (6-7 weeks old). Six newborn and five juvenile animals were subjected to a severe fluid-percussion (FP) induced TBI. The remaining animals were used as sham operated untreated control groups. Simultaneously, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rates of oxygen and glucose were determined. At 1 h after FP-TBI, [18F]FDOPA was infused and PET scanning was performed for 2 h. At 2 h after FP-TBI administration, a second series of measurements of physiological values including CBF and brain oxidative metabolism data had been obtained. Severe FP-TBI elicited a marked increase in the rate constant for fluorodopamine production (k3FDOPA) in all brain regions of newborn piglets studied by between 97% (mesencephalon) and 143% (frontal cortex) (p < 0.05). In contrast, brain hemodynamics and cerebral oxidative metabolism remained unaltered after TBI. Furthermore, the permeability-surface area product of FDOPA (PSFDOPA) was unchanged. In addition, regional blood flow differences between corresponding ipsi- and contralateral brain regions did not occur after TBI. Thus, it is suggested that severe FP-TBI induces an upregulation of AADC activity of newborn piglets that is not related to alterations in brain oxidative metabolism.
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http://dx.doi.org/10.1089/0897715041651024DOI Listing
August 2004

Developmental changes in the activities of aromatic amino acid decarboxylase and catechol-O-methyl transferase in the porcine brain: a positron emission tomography study.

Neurosci Lett 2004 Jul;364(3):159-63

Institut für Interdisziplinäre Isotopenforschung, Permoserstrasse 15, D-04318 Leipzig, Germany.

Newborn (7-10 days old) and young (6-8 weeks old) pigs were used to study the metabolism of 6-[18F]fluoro-L-DOPA (FDOPA) in various brain regions with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the rate constants for the decarboxylation of FDOPA (k3) and for the metabolism of the resulting [18F]fluoro-dopamine (kcl). Whereas general physiological parameters such as cerebral blood flow, cerebral oxygen uptake, arterial blood gases and glucose concentration remained unchanged in young pigs as compared to newborns, a 50-200% increase of k3 in frontal cortex, striatum and mesencephalon was found. Also a 60% enhancement of kcl in the frontal cortex was measured, which is related to changes of the catechol-O-methyl-transferase (COMT) activity and implies a special function of this enzyme in the development of this brain region. In addition, measurement of plasma metabolites of FDOPA with HPLC was performed. The metabolism of FDOPA in young pigs was significantly faster than in newborns. Calculation of the rate constant for O-methylation of FDOPA by COMT revealed a significant elevation of this enzyme activity in young pigs compared to newborns. The increase of AADC and COMT activity with brain development is considered to be associated with special stages of neuronal maturation and tissue differentiation.
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http://dx.doi.org/10.1016/j.neulet.2004.04.041DOI Listing
July 2004

Tris(azolyl)methylthiolates: Another New Scorpionate Class?

Angew Chem Int Ed Engl 2001 Apr;40(7):1247-1249

Institut für Anorganische und Physikalische Chemie Universität Bremen Postfach 330440, 28334 Bremen (Germany).

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April 2001