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Christoph Müller

Publications and source records attributed to Christoph Müller.

12 recordsLinked to original sources
PubMed2007

Total synthesis and evaluation of the actin-binding properties of microcarpalide and a focused library of analogues.

A comparative investigation shows that hydroxylated 10-membered lactones modeled around the fungal metabolites microcarpalide (1) and pinolidoxin (2) are endowed with selective actin-binding properties. Although less potent than the marine natural product latrunculin A, which represents the standard in the field, nonenolides of this type are significantly less toxic and accommodate substantial structural editing. Most notable is the fact that even an intramolecular transesterification with formation of a hydroxylated butanolide skeleton does not annihilate their microfilament disrupting capacity. This finding calls for a reinvestigation of the biological profile of other fungal metabolites that embody a similar motif. Microcarpalide (1) serving as the calibration point for this comparative study was prepared by total synthesis based on ring-closing metathesis (RCM) as the key step. The chosen route favorably compares to previous approaches to this target and provides further support for the notion that the (E,Z)-configuration of a medium-sized cycloalkene can be controlled by proper choice of the catalyst as previously outlined by our group. 9-epi-Microcarpalide 26 and furanone 27 as representative examples of the "natural productlike" compounds investigated herein have been characterized by crystal structure analysis.

4-Butyrolactone↗
PubMed2006

Quantitative precursor studies on di- and trihydroxybenzene formation during coffee roasting using "in bean" model experiments and stable isotope dilution analysis.

The objective of this study was to investigate the potential of various raw bean components as precursors of pyrogallol (1), hydroxyhydroquinone (2), catechol (3), 4-ethylcatechol (4), 4-methylcatechol (5), and 3-methylcatechol (6) under quasi "natural" roasting conditions by using the recently developed "in bean" model roast experiments. Freeze-dried, fully extracted bean shells were loaded with aqueous solutions of either single coffee compounds or fractions isolated from the raw bean solubles. After freeze-drying, these reconstituted beans were roasted, aqueous coffee brews were prepared, and the target phenols were quantified by means of a stable isotope dilution assay with LC-MS/MS detection. On the basis of the quantitative data, it can be concluded that upon coffee bean roasting, catechol (3) is primarily formed by degradation of caffeoylquinic acids from both the caffeic acid and the quinic acid moiety of the molecule, as well as from Maillard-type reactions from carbohydrates and amino acids. In contrast, pyrogallol (1) and hydroxyhydroquinone (2) are efficiently generated from carbohydrates and amino acids and, in addition, from free or chlorogenic acid bound quinic acid moieties. 4-Ethylcatechol (4) is exclusively generated upon thermal breakdown of caffeic acid moieties. 3-Methylcatechol (6) is formed primarily from the Maillard reactions and, to a minor extent, also from various phenolic precursors, whereas 4-methylcatechol (5) is produced in trace amounts only from all of the different precursors investigated. On the basis of this precursor study, reaction routes explaining the formation of the target phenols are proposed.

Catechols↗
PubMed2006

Synthesis and structure determination of covalent conjugates formed from the sulfury-roasty-smelling 2-furfurylthiol and di- or trihydroxybenzenes and their identification in coffee brew.

Recent investigations demonstrated that the reaction of odor-active thiols such as 2-furfurylthiol with thermally generated chlorogenic acid degradation products is responsible for the rapid aroma staling of coffee beverages. To get a clear understanding of the molecular mechanisms underlying this aroma staling, the existence of putative phenol/thiol conjugates needs to be verified in coffee. The aim of the present study was therefore to synthesize such conjugates for use as reference substances for LC-MS screening of coffee. To achieve this, catechol, 3-methyl-, 4-methyl-, and 4-ethylcatechol, pyrogallol, hydroxyhydroquinone, 5-O-caffeoylquinic acid, and caffeic acid, respectively, were reacted with 2-furfurylthiol in the presence of iron(III) chloride and air oxygen. After purification, the structures of 25 phenol/thiol conjugates were identified by means of LC-MS/MS and 1D/2D NMR experiments. Using these compounds as reference materials, four conjugates, namely, 3-((2-furylmethyl)sulfanyl)catechol, 3-((2-furylmethyl)sulfanyl)-5-ethylcatechol, 4-((2-furylmethyl)sulfanyl)hydroxyhydroquinone, and 3,4-bis((2-furylmethyl)sulfanyl) hydroxyhydroquinone, were identified for the first time in coffee brew by means of HPLC-MS/MS(MRM). These findings clearly demonstrate catechol, 4-ethylcatechol, and hydroxyhydroquinone as the primary thiol trapping agents involved in the aroma staling of coffee beverages.

Chromatography, High Pressure Liquid↗
PubMed2006

MRI and discography in traumatic intervertebral disc lesions.

In this study we evaluated magnetic resonance imaging (MRI) in trauma patients for assessing traumatised adjacent discs of fractured vertebrae before dorsoventral stabilisation. In a prospective study, MRI of 54 discs was performed with a 1.5-T MRI unit. The preoperative MRI with sagittal T1-W-SE and T2-W-TSE was compared to intraoperative discography, which was carried out on both intervertebral discs adjacent to the fractured vertebrae. Signal alterations, morphological changes in the adjacent discs, fractured vertebrae and associated ligament injuries were evaluated. In 47/54 (87%) of the intervertebral discs, the results of both imaging findings were concordant. The discs adjoining vertebral fractures were normal in 18 cases. Regarding the positive concordant imaging findings, MRI and discography revealed traumatised adjacent cranial and caudal discs in 22 discs. In 7 cases, only the cranial adjacent disc was affected. Moreover, 17 cases of intradiscal bleeding, 13 intraosseous herniations into the fractured vertebrae and 20 anuluar tears were visualised in MRI. Associated ligament injuries were detected in 18 cases. Findings were discordant in eight discs. In six discs, MRI was abnormal, demonstrating signal alterations suggestive of positive imaging findings, whereas discography demonstrated no disc injury. MRI failed to detect disc injury in two discs, whereas discography was positive, showing an irregular intradiscal contrast media distribution. MRI, as a non-invasive method for assessing fractures of the thoraco-lumbar spine, may detect traumatised adjacent intervertebral discs. MRI is superior to intraoperative discography. The performance of MRI of the thoraco-lumbar spine is recommended before dorsoventral stabilisation in trauma patients, as it can reveal additional preoperative information such as fractures, disc and associated ligament injuries.

Adolescent↗
PubMed2006

Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II.

Griscelli syndrome (GS) was diagnosed in a 2-year-old patient with oculocutaneous albinism and immunodeficiency, but sequencing of RAB27a revealed only a heterozygous mutation. Due to impaired natural killer (NK) and T-cell cytotoxicity implying a high risk of developing hemophagocytic lymphohistiocytosis (HLH), he was prepared for hematopoietic stem cell transplantation (HSCT). Unexpectedly, a severe bleeding episode occurred that led to the demonstration of disturbed platelet aggregation, reduced plateletdense granules, and impaired platelet degranulation. In combination with neutropenia, this suggested the diagnosis of Hermansky-Pudlak syndrome type II (HPSII) and a novel homozygous mutation in AP3B1 was detected. None of the 3 reported HPSII patients had developed HLH, and our patient seroconverted to Epstein-Barr virus (EBV) without clinical symptoms. HSCT was therefore withheld, and granulocyte-colony-stimulating factor (G-CSF) therapy was initiated and prevented further bacterial infections. At 3 years of age, however, the patient developed, without an obvious trigger, fulminant HLH that was resistant to therapy. This patient shows that careful clinical and molecular diagnosis is essential to differentiate the complex disorders of lysosomal trafficking. HPSII belongs to the group of familial hemophagocytic syndromes and may represent an indication for HSCT.

Adaptor Protein Complex 3↗
PubMed2005

Total synthesis of aspercyclide C.

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide.

Lactones↗
PubMed2005

Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons.

Whole-cell patch-clamp recordings from cultured rat dorsal root ganglion neurons demonstrated that the P2Y1 receptor agonists adenosine 5'-O-2-thiodiphosphate (ADP-beta-S) and 2-methylthio adenosine 5'-diphosphate (2-MeSADP) inhibit the alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP)-induced P2X3 receptor-currents. This effect could be antagonized by the wide-spectrum G protein blocker GDP-beta-S and the P2Y(1) receptor antagonist MRS 2179. The P2Y12,13 receptor antagonist AR-C6993MX and pertussis toxin, a blocker of Galphai/o, did not interact with the effect of ADP-beta-S. Hence, the results indicate that ADP-sensitive P2Y1 receptors of rat dorsal root ganglion neurons inhibit ionotropic P2X3 receptors via G protein-activation.

Adenosine Diphosphate↗
PubMed2005

Screening of raw coffee for thiol binding site precursors using "in bean" model roasting experiments.

The purpose of the following study was to investigate the influence of coffee roasting on the thiol-binding activity of coffee beverages, and to investigate the potential of various green bean compounds as precursors of thiol-binding sites by using promising "in bean" model roast experiments. Headspace gas chromatographic analysis on coffee brews incubated in the presence of the roasty-sulfury smelling 2-furfurylthiol for 20 min at 30 degrees C in septum-closed vessels revealed that the amounts of "free" thiol decreased drastically with increasing the roasting degree of the beans used for preparation of the brews. A half-maximal binding capacity (BC(50)) of 183 mg of 2-furfurylthiol per liter of standard coffee beverage was determined for a roasted coffee (CTN value of 67), thus demonstrating that enormous amounts of the odor-active thiol are "bound" by the coffee. Furthermore, biomimetic "in bean" precursor experiments have been performed in order to elucidate the precursor for the thiol-binding sites in the raw coffee bean. These experiments opened the possibility of studying coffee model reactions under quasi-natural roasting conditions and undoubtedly identified chlorogenic acids as well as thermal degradation products caffeic acid and quinic acid as important precursors for low-molecular-weight thiol-binding sites. In particular, when roasted in the presence of transition metal ions, chlorogenic acids and even more caffeic acid showed thiol-binding activity which was comparable to the activity measured for the authentic coffee brew.

Binding Sites↗
PubMed2004

Steric and electronic effects in cyclic alkoxyamines--synthesis and applications as regulators for controlled/living radical polymerization.

The synthesis of new six- and seven-membered cyclic alkoxyamines bearing ethyl groups at the alpha-N position of the alkoxyamines is described. The key step in the synthesis of the sterically hindered six-membered cyclic alkoxyamines is a Wadsworth-Horner-Emmons olefination with bisphosphonate 1. The seven-membered cyclic alkoxyamines were prepared from the corresponding six-membered keto alkoxyamines by ring-enlargement with trimethylsilyl(TMS)-diazomethane. The use of the new alkoxyamines as regulators/initiators for radical polymerization is discussed. Efficient controlled and living polymerization of styrene and n-butyl acrylate was obtained with the six-membered tetraethyl alkoxyamine 13. Controlled polymerizations can be conducted even at 90 degrees C. In addition, alkoxyamine 13 can be used for the preparation of AB diblock and ABA triblock copolymers with narrow polydispersities. The influence of the replacement of methyl groups in the alpha-position of the N atom in cyclic alkoxyamines by larger ethyl groups on the styrene polymerization (reaction time, PDI, kinetics of the C-O bond homolysis) is discussed. In addition, thermal decomposition of the new alkoxyamines was studied. Furthermore, the synthesis of N,N-bissilylated alkoxyamines is described. The silylated alkoxyamines are not suitable as regulators/initiators for the controlled/living radical polymerization. The C-O bonds in silylated alkoxyamines are stronger than the C-O bonds in analogous N,N-dialkylated alkoxyamines. The experimental results are verified by calculations with Gaussian 98 (A. 9).

Journal Article↗
PubMed2004

Effects of hemodialysis, dialyser type and iron infusion on oxidative stress in uremic patients.

Uremic patients undergoing hemodialysis (HD) are considered to face an elevated risk for atherosclerosis and cancer. This has been attributed in part to an increased oxidative stress. In this pilot study, oxidative cell damage in blood of HD-patients was compared to those of controls: total DNA damage (basic and specific oxidative DNA damage), modulation of glutathione levels (total and oxidized glutathione) and of lipid peroxidation were monitored via the Comet assay (with and without FPG), a kinetic photometric assay and HPLC quantification of plasma malondialdehyde (MDA), respectively. In some samples, leukocytes were analysed for malondialdehyde-deoxyguanosine-adducts (M1dG) with an immunoslot blot technique. HD-patients (n=21) showed a significant increase of total DNA damage (p<10(-12)), compared to controls (n=12). In a subset of patients and controls, GSSG levels and M1dG, however, only increased slightly, while tGSH and MDA levels did not differ. The influence of different low flux HD-membranes was tested in a pilot study with nine patients consecutively dialysed on three membrane types for four weeks each. In addition to the individual disposition of the patient, the dialyser membrane had a significant impact on oxidative stress. Total DNA damage was found to be almost identical for polysulfone and vitamin E coated cellulosic membranes, whereas a slight, but significant increase was observed with cellulose-diacetate (p<0.001). In patients receiving iron infusion during HD, MDA-formation (n=11) and total DNA damage (n=10) were additionally increased (p<0.005). Our results show an increased oxidative damage in HD-patients, compared to healthy volunteers. Significant influences were found for the dialyser membrane type and iron infusion.

Adult↗
PubMed2003

The effect of optical devices and repeated trials on the velocity of saccadic eye movements.

OBJECTIVE: The purpose of this prospective study was to analyze the effect of glasses and contact lenses on the latency and velocity of visually evoked saccadic eye movements. MATERIAL AND METHODS: A saccadic test was performed 10 times on 20 emmetropic controls (Group A) and 20 ametropic test subjects with myopia (Group B) who were using glasses (Subgroup Bg) or contact lenses (Subgroup Bc). RESULTS: No training or fatigue effect on either latency or eye velocity was registered. Regardless of visual acuity (Group A or B) or of the optical device used (Subgroup Bg or Bc), no significant intergroup difference in latency could ultimately be established. Subgroup Bc showed a significantly slower eye velocity than Group A. Regardless of the optical device used, subjects with a higher degree of myopia (> 6 D) showed a lower eye velocity than the Group A controls. Additionally, saccadic velocity was lower in this subgroup ( > 6 D) in subjects using contact lenses than in those using glasses. CONCLUSION: These results demonstrate that optical devices have an influence on the electronystagmographical analyses of the vestibulo-ocular reflex that must be taken into consideration, particularly in scientific investigations.

Adult↗