112 results on '"Neier, A."'
Search Results
2. Perinatal DEHP exposure induces sex- and tissue-specific DNA methylation changes in both juvenile and adult mice
- Author
-
Tamara R. Jones, Christine A Rygiel, Justin A. Colacino, Maureen A. Sartor, Dana C. Dolinoy, Laurie K. Svoboda, Siyu Liu, Kari Neier, Kai Wang, and Raymond G. Cavalcante
- Subjects
0301 basic medicine ,endocrine system ,mouse model ,Health, Toxicology and Mutagenesis ,Bisulfite sequencing ,Population ,Weanling ,010501 environmental sciences ,Biology ,liver ,01 natural sciences ,Andrology ,03 medical and health sciences ,chemistry.chemical_compound ,blood ,Genetics ,Endocrine system ,Juvenile ,Epigenetics ,education ,Molecular Biology ,perinatal ,Genetics (clinical) ,0105 earth and related environmental sciences ,DEHP exposure ,education.field_of_study ,DNA methylation ,Phthalate ,030104 developmental biology ,chemistry ,bisulfite sequencing ,AcademicSubjects/SCI02302 ,Research Article - Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a type of phthalate plasticizer found in a variety of consumer products and poses a public health concern due to its metabolic and endocrine disruption activities. Dysregulation of epigenetic modifications, including DNA methylation, has been shown to be an important mechanism for the pathogenic effects of prenatal exposures, including phthalates. In this study, we used an established mouse model to study the effect of perinatal DEHP exposure on the DNA methylation profile in liver (a primary target tissue of DEHP) and blood (a common surrogate tissue) of both juvenile and adult mice. Despite exposure ceasing at 3 weeks of age (PND21), we identified thousands of sex-specific differential DNA methylation events in 5-month old mice, more than identified at PND21, both in blood and liver. Only a small number of these differentially methylated cytosines (DMCs) overlapped between the time points, or between tissues (i.e. liver and blood), indicating blood may not be an appropriate surrogate tissue to estimate the effects of DEHP exposure on liver DNA methylation. We detected sex-specific DMCs common between 3-week and 5-month samples, pointing to specific DNA methylation alterations that are consistent between weanling and adult mice. In summary, this is the first study to assess the genome-wide DNA methylation profiles in liver and blood at two different aged cohorts in response to perinatal DEHP exposure. Our findings cast light on the implications of using surrogate tissue instead of target tissue in human population-based studies and identify epigenetic biomarkers for DEHP exposure.
- Published
- 2021
3. Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure
- Author
-
Kai Wang, Kari Neier, Laurie K. Svoboda, Raymond G. Cavalcante, Dana C. Dolinoy, Justin A. Colacino, and Maureen A. Sartor
- Subjects
Environmental and Nutritional Epigenetics ,phthalate ,sex differences ,0301 basic medicine ,DNA methylation ,lcsh:QH426-470 ,Developmental origins of health and disease (DOHaD) ,Plasticizer ,Phthalate ,Physiology ,heart ,030204 cardiovascular system & hematology ,Biology ,Biochemistry ,Sex specific ,03 medical and health sciences ,chemistry.chemical_compound ,lcsh:Genetics ,030104 developmental biology ,0302 clinical medicine ,chemistry ,toxicoepigenetics ,Genetics ,Original Research - Abstract
Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.
- Published
- 2020
4. Tissue- and Sex-Specific DNA Methylation Changes in Mice Perinatally Exposed to Lead (Pb)
- Author
-
Kai Wang, Siyu Liu, Laurie K. Svoboda, Christine A. Rygiel, Kari Neier, Tamara R. Jones, Justin A. Colacino, Dana C. Dolinoy, and Maureen A. Sartor
- Subjects
0301 basic medicine ,lcsh:QH426-470 ,Biology ,ERRBS ,Andrology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,lead exposure ,Genetics ,sex ,Epigenetics ,Genetics (clinical) ,Epigenomics ,DNA methylation ,tissue ,Brief Research Report ,lcsh:Genetics ,030104 developmental biology ,Differentially methylated regions ,chemistry ,030220 oncology & carcinogenesis ,Reduced representation bisulfite sequencing ,Molecular Medicine ,Genomic imprinting ,DNA ,Toxicant - Abstract
Lead (Pb) is a well-known toxicant that interferes with the development of a child's nervous and metabolic systems and increases the risk of developing diseases later in life. Although studies have investigated epigenetic effects associated with Pb exposure, knowledge of genome-wide changes with in vivo low dose perinatal Pb exposure in multiple tissues is limited. Within the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium, we utilized a mouse model to investigate tissue- and sex-specific DNA methylation. Dams were assigned to control or Pb-acetate water, respectively. Exposures started 2 weeks prior to mating and continued until weaning at post-natal day 21 (PND21). Liver and blood were collected from PND21 mice, and the DNA methylome was assessed using enhanced reduced representation bisulfite sequencing (ERRBS). We identified ∼1000 perinatal Pb exposure related differentially methylated cytosines (DMCs) for each tissue- and sex-specific comparison, and hundreds of tissue- and sex-specific differentially methylated regions (DMRs). Several mouse imprinted genes were differentially methylated across both tissues in males and females. Overall, our findings demonstrate that perinatal Pb exposure can induce tissue- and sex-specific DNA methylation changes and provide information for future Pb studies in humans.
- Published
- 2020
5. Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice
- Author
-
Dana C. Dolinoy, Leah D. Bedrosian, D Cheatham, and Kari Neier
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Dibutyl phthalate ,Offspring ,Phthalic Acids ,Medicine (miscellaneous) ,Weanling ,030209 endocrinology & metabolism ,Weaning ,Article ,Epigenesis, Genetic ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Sex Factors ,0302 clinical medicine ,Pregnancy ,Internal medicine ,medicine ,Animals ,Epigenetics ,030219 obstetrics & reproductive medicine ,Diisononyl phthalate ,Perinatal Exposure ,Body Weight ,Phthalate ,Gene Expression Regulation, Developmental ,Organ Size ,DNA Methylation ,Genes, Intracisternal A-Particle ,Endocrinology ,chemistry ,Models, Animal ,DNA methylation ,Female - Abstract
Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (Avy) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposedAvy/aoffspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs.
- Published
- 2018
6. Physician decision making in selection of second-line treatments in immune thrombocytopenia in children
- Author
-
Carolyn M. Bennett, Amy Geddis, Kristin A. Shimano, Vicky R. Breakey, James B. Bussel, Alexis A. Thompson, Kristina M. Haley, Ellis J. Neufeld, Jennifer A. Rothman, Adonis Lorenzana, Rachael F. Grace, Michael Jeng, George R. Buchanan, Kerry Hege, Shelley E. Crary, Jenny M. Despotovic, Michelle Neier, Cindy E. Neunert, Robert J. Klaassen, Yves D. Pastore, Melissa J. Rose, Travis Brown, Michele P. Lambert, and Peter W. Forbes
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Side effect ,medicine.medical_treatment ,Clinical Decision-Making ,Decision Making ,Splenectomy ,MEDLINE ,Eltrombopag ,Physician Decision ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacotherapy ,Physicians ,hemic and lymphatic diseases ,medicine ,Humans ,Child ,Purpura, Thrombocytopenic, Idiopathic ,business.industry ,Hematology ,chemistry ,030220 oncology & carcinogenesis ,Female ,Observational study ,Rituximab ,business ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.
- Published
- 2018
7. An Efficient Synthetic Approach to Calix[n]furan[4-n]pyrroles and the Calix[n]tetrahydrofuran[4-n]pyrrolidines
- Author
-
Reinhard Neier, William Maupillier, Guillaume Journot, and Helen Stoeckli-Evans
- Subjects
010405 organic chemistry ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Furan ,Calixarene ,Hydrogenation reaction ,Organic chemistry ,Physical and Theoretical Chemistry ,Tetrahydrofuran - Abstract
A scalable synthesis of calix[n]furan[4-n]pyrroles and their fully reduced analogues, the novel calix[n]tetrahydrofuran[4-n]pyrrolidines obtained by hydrogenation of their aromatic relatives, was developed and optimized. The hydrogenation reaction was studied at several selected pressures (P = 100, 50 and 15 bars) and high diastereoselectivity was observed for the four possible calix[n]tetrahydrofuran[4-n]pyrrolidines. Moreover, two of the saturated macrocycles were obtained with good overall yields starting from the easily accessible calix[4]furan. The conformation of the eight macrocycles was analysed by X-ray diffraction and while a classical 1,3-alternate conformation of this type of compound was observed for the aromatic macrocycles, two distinct types of conformation were observed with the calix[n]tetrahydrofuran[4-n]pyrrolidines.
- Published
- 2017
8. Perinatal exposure to lead results in altered DNA methylation in adult mouse liver and blood: Implications for target versus surrogate tissue use in environmental epigenetics
- Author
-
Raymond G. Cavalcante, Justin A. Colacino, Tamara R. Jones, Zing Tsung-Yeh Tsai, Claudia Lalancette, Dana C. Dolinoy, Shue Liu, Maureen A. Sartor, Laurie K. Svoboda, Kari Neier, and Jaclyn M. Goodrich
- Subjects
0303 health sciences ,Perinatal Exposure ,Bisulfite sequencing ,Biology ,3. Good health ,Andrology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Differentially methylated regions ,chemistry ,13. Climate action ,Transcription (biology) ,DNA methylation ,Epigenetics ,030217 neurology & neurosurgery ,030304 developmental biology ,Epigenomics ,Toxicant - Abstract
BackgroundDNA methylation is a critical epigenetic mechanism linking early developmental environment to long-term health. In humans, the extent to which toxicant-induced changes in DNA methylation in surrogate tissues, such as blood, mirror those in the target tissues is unclear. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues.ObjectivesThe objective of this study was to investigate the effects of perinatal exposure to a human environmentally relevant level (32 ppm in maternal drinking water) of lead (Pb) on liver and blood DNA methylation in adult male and female mice. We hypothesized that developmental Pb exposure would lead to persistent changes in DNA methylation, and that a subset of differentially methylated loci would overlap between liver and blood.MethodsEnhanced reduced-representation bisulfite sequencing was used to assess DNA methylation in 5 month old Pb-exposed and control mice. Sex-stratified modeling of differential methylation by Pb exposure was conducted using an established bioinformatics pipeline.ResultsAlthough Pb exposure ceased at 3 weeks of age, we observed thousands of stably modified, sex-specific differentially methylated regions in the blood and liver of Pb-exposed animals, including 44 genomically imprinted loci. In males, we discovered 5 sites that overlapped between blood and liver, and exhibited changes in DNA methylation in the same direction in both tissues.ConclusionsThese data demonstrate that perinatal exposure to Pb induces sex-specific changes in hepatic DNA methylation in adulthood, some of which are also present in blood. Ongoing studies will provide additional exposure-specific insights, and include other epigenetic marks that will enable further refinement of the design and analysis of human studies where target tissues are inaccessible.
- Published
- 2019
- Full Text
- View/download PDF
9. Quantification of Protein Interaction Network Dynamics using Multiplexed Co-Immunoprecipitation
- Author
-
Adam G. Schrum, Steven C Neier, Claudia Neuhauser, Emily A. Brown, and Stephen E. P. Smith
- Subjects
Fluorophore ,Immunoprecipitation ,General Chemical Engineering ,T-Lymphocytes ,02 engineering and technology ,010402 general chemistry ,Proteomics ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Antibodies ,Flow cytometry ,Protein–protein interaction ,chemistry.chemical_compound ,Lysis buffer ,medicine ,Humans ,Multiplex ,Protein Interaction Maps ,Neurons ,General Immunology and Microbiology ,medicine.diagnostic_test ,General Neuroscience ,Proteins ,021001 nanoscience & nanotechnology ,Flow Cytometry ,Microspheres ,0104 chemical sciences ,chemistry ,Biophysics ,0210 nano-technology ,Signal Transduction - Abstract
Dynamic protein-protein interactions control cellular behavior, from motility to DNA replication to signal transduction. However, monitoring dynamic interactions among multiple proteins in a protein interaction network is technically difficult. Here, we present a protocol for Quantitative Multiplex Immunoprecipitation (QMI), which allows quantitative assessment of fold changes in protein interactions based on relative fluorescence measurements of Proteins in Shared Complexes detected by Exposed Surface epitopes (PiSCES). In QMI, protein complexes from cell lysates are immunoprecipitated onto microspheres, and then probed with a labeled antibody for a different protein in order to quantify the abundance of PiSCES. Immunoprecipitation antibodies are conjugated to different MagBead spectral regions, which allows a flow cytometer to differentiate multiple parallel immunoprecipitations and simultaneously quantify the amount of probe antibody associated with each. QMI does not require genetic tagging and can be performed using minimal biomaterial compared to other immunoprecipitation methods. QMI can be adapted for any defined group of interacting proteins, and has thus far been used to characterize signaling networks in T cells and neuronal glutamate synapses. Results have led to new hypothesis generation with potential diagnostic and therapeutic applications. This protocol includes instructions to perform QMI, from the initial antibody panel selection through to running assays and analyzing data. The initial assembly of a QMI assay involves screening antibodies to generate a panel, and empirically determining an appropriate lysis buffer. The subsequent reagent preparation includes covalently coupling immunoprecipitation antibodies to MagBeads, and biotinylating probe antibodies so they can be labeled by a streptavidin-conjugated fluorophore. To run the assay, lysate is mixed with MagBeads overnight, and then beads are divided and incubated with different probe antibodies, and then a fluorophore label, and read by flow cytometry. Two statistical tests are performed to identify PiSCES that differ significantly between experimental conditions, and results are visualized using heatmaps or node-edge diagrams.
- Published
- 2019
10. Longitudinal Metabolic Impacts of Perinatal Exposure to Phthalates and Phthalate Mixtures in Mice
- Author
-
Kari Neier, Leah D. Bedrosian, Peter X.-K. Song, Drew Cheatham, Brigid Gregg, and Dana C. Dolinoy
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Dibutyl phthalate ,Phthalic Acids ,010501 environmental sciences ,01 natural sciences ,Body fat percentage ,Increased body fat percentage ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Endocrinology ,Adipokines ,Plasticizers ,Pregnancy ,Internal medicine ,Diethylhexyl Phthalate ,Glucose Intolerance ,medicine ,Animals ,Caenorhabditis elegans Proteins ,Research Articles ,0105 earth and related environmental sciences ,Diisononyl phthalate ,Perinatal Exposure ,business.industry ,Phthalate ,Lipase ,medicine.disease ,Dibutyl Phthalate ,030104 developmental biology ,chemistry ,Prenatal Exposure Delayed Effects ,Lean body mass ,Body Composition ,Female ,Metabolic syndrome ,business - Abstract
Developmental exposures to phthalates are suspected to contribute to risk of metabolic syndrome. However, findings from human studies are inconsistent, and long-term metabolic impacts of early-life phthalate and phthalate mixture exposures are not fully understood. Furthermore, most animal studies investigating metabolic impacts of developmental phthalate exposures have focused on diethylhexyl phthalate (DEHP), whereas newer phthalates, such as diisononyl phthalate (DINP), are understudied. We used a longitudinal mouse model to evaluate long-term metabolic impacts of perinatal exposures to three individual phthalates, DEHP, DINP, and dibutyl phthalate (DBP), as well as two mixtures (DEHP+DINP and DEHP+DINP+DBP). Phthalates were administered to pregnant and lactating females through phytoestrogen-free chow at the following exposure levels: 25 mg of DEHP/kg of chow, 25 mg of DBP/kg of chow, and 75 mg of DINP/kg of chow. One male and female per litter (n = 9 to 13 per sex per group) were weaned onto control chow and followed until 10 months of age. They underwent metabolic phenotyping at 2 and 8 months, and adipokines were measured in plasma collected at 10 months. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females. Phthalate-exposed males did not exhibit statistically significant differences in the measured longitudinal metabolic outcomes. Surprisingly, perinatal phthalate mixture exposures were statistically significantly associated with few metabolic effects and were not associated with larger effects than single exposures, revealing complexities in metabolic effects of developmental phthalate mixture exposures.
- Published
- 2019
11. Characterization of the mouse white adipose tissue redox environment and associations with perinatal environmental exposures to bisphenol A and high-fat diets
- Author
-
Kari Neier, Elizabeth M. Marchlewicz, Leah D. Bedrosian, Craig Harris, and Dana C. Dolinoy
- Subjects
0301 basic medicine ,Male ,Bisphenol A ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,White adipose tissue ,Diet, Mediterranean ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Longitudinal Studies ,Chromatography, High Pressure Liquid ,Adiposity ,chemistry.chemical_classification ,Nutrition and Dietetics ,food and beverages ,Glutathione ,Prenatal Exposure Delayed Effects ,Female ,Oxidation-Reduction ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,Adipose Tissue, White ,030209 endocrinology & metabolism ,Diet, High-Fat ,Redox ,Article ,03 medical and health sciences ,Phenols ,Internal medicine ,medicine ,Animals ,Cysteine ,Obesity ,Benzhydryl Compounds ,Molecular Biology ,Reactive oxygen species ,Mouse White Adipose Tissue ,Body Weight ,nutritional and metabolic diseases ,High fat diet ,Environmental Exposure ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,chemistry ,Diet, Western - Abstract
White adipose tissue (WAT) plays an important role in obesity pathophysiology. Redox signaling underlies several aspects of WAT physiology; however, the thiol redox environment of WAT has not yet been fully characterized. Dietary and endocrine disrupting chemical (EDC) exposures during development can transiently impact the cellular redox environment, but it is unknown whether these exposures can reprogram the WAT thiol redox environment. To characterize the WAT thiol redox environment, we took a descriptive approach and measured thiol redox parameters using high-performance liquid chromatography in mouse mesenteric (mWAT), gonadal (gWAT) and subinguinal (sWAT) depots. Cysteine (CYSS:CYS) and glutathione (GSSG:GSH) redox potentials (Eh) were more oxidizing in gWAT and sWAT than mWAT. Increased body weight, relative WAT weight and age were associated with oxidizing GSSG:GSH Eh in mWAT in a sex-specific manner. Body weight and relative WAT weight were also positively associated with GSSG:GSH Eh in sWAT. We carried out a second mouse study with perinatal exposures to bisphenol A (BPA) and Mediterranean and Western high-fat diets (HFDs) to determine whether early-life chemical and dietary factors have long-lasting impacts on mWAT redox parameters. Mice exposed to Mediterranean HFD or BPA had more oxidizing GSSG:GSH mWAT Eh than controls, with more pronounced differences in females. These findings suggest an important role for the thiol redox environment in WAT physiology. Observed sex-specific and depot-specific differences in thiol redox parameters are consistent with known WAT physiology. Lastly, mWAT GSSG:GSH Eh may be reprogrammed by developmental exposure to HFDs and EDCs, which may have implications for obesity risk.
- Published
- 2019
12. The priming molecule β ‐aminobutyric acid is naturally present in plants and is induced by stress
- Author
-
Damien Thevenet, Ivan Baccelli, Reinhard Neier, Brigitte Mauch-Mani, Gaétan Glauser, Andrea Balmer, Armelle Vallat, and Victoria Pastor
- Subjects
0106 biological sciences ,0301 basic medicine ,abiotic stress ,beta-aminobutyric acid (BABA) ,Physiology ,Priming (immunology) ,Endogeny ,Plant Science ,Biology ,Plant Roots ,01 natural sciences ,Aminobutyric acid ,Mass Spectrometry ,stable isotope quantification ,03 medical and health sciences ,chemistry.chemical_compound ,biotic stress ,Stress, Physiological ,Arabidopsis thaliana ,chemistry.chemical_classification ,Abiotic stress ,Aminobutyrates ,fungi ,Reproducibility of Results ,BABA-induced resistance ,food and beverages ,Plants ,Reference Standards ,Biotic stress ,biology.organism_classification ,Amino acid ,Plant Leaves ,030104 developmental biology ,Biochemistry ,chemistry ,UHPLC-MS/MS ,priming of defense ,Xenobiotic ,Chromatography, Liquid ,010606 plant biology & botany - Abstract
The defense system of a plant can be primed for increased defense, resulting in an augmented stress resistance and/or tolerance. Priming can be triggered by biotic and abiotic stimuli, as well as by chemicals such as β-aminobutyric acid (BABA), a nonprotein amino acid considered so far a xenobiotic. Since the perception mechanism of BABA has been recently identified in Arabidopsis thaliana, in the present study we explored the possibility that plants do synthesize BABA. After developing a reliable method to detect and quantify BABA in plant tissues, and unequivocally separate it from its two isomers α- and γ-aminobutyric acid, we measured BABA levels in stressed and nonstressed A. thaliana plants, and in different plant species. We show that BABA is a natural product of plants and that the endogenous levels of BABA increase rapidly after infection with necrotrophic, biotrophic and hemibiotrophic pathogens, as well as after salt stress and submergence. Our results place the rise in endogenous BABA levels to a point of convergence in plant stress response and provide biological significance to the presence of a receptor in plants. These findings can explain the extremely widespread efficacy of BABA and open the way to unravel the early steps of priming.
- Published
- 2016
13. Applications of Tandem Diels-Alder/Sigmatropic Rearrangement Reactions to Natural Product Synthesis
- Author
-
Reinhard Neier and Ewa Banach
- Subjects
chemistry.chemical_compound ,Natural product ,chemistry ,Tandem ,010405 organic chemistry ,Organic Chemistry ,Diels alder ,Organic chemistry ,Sigmatropic reaction ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Published
- 2016
14. The NMR characterization of locked conformations of two stereoisomers of calix[4]tetrahydrofuran
- Author
-
Guillaume Journot, Damien Thevenet, Helen Stoeckli-Evans, and Reinhard Neier
- Subjects
chemistry.chemical_compound ,010405 organic chemistry ,Chemistry ,NMR spectroscopy of stereoisomers ,Organic chemistry ,General Materials Science ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Tetrahydrofuran ,0104 chemical sciences ,Characterization (materials science) - Published
- 2016
15. Corrin Syntheses. Part VI
- Author
-
Peter Löliger, Brian Pace, Kasturi Srinivasachar, Walter Fuhrer, John G. Gleason, Walter Hunkeler, Albert Eschenmoser, Hans‐Jakob Wild, Larry Ellis, Pius Wehrli, Bernard T. Golding, Erwin Götschi, Yasuji Yamada, Niklaus Buhler, René Nordmann, Peter Schneider, Reinhart Keese, Klaus Müller, Dusan Miljkovic, and Reinhard Neier
- Subjects
chemistry.chemical_classification ,Sulfide ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Corrin ,Closure (topology) ,Chromophore ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Biochemistry ,Catalysis ,0104 chemical sciences ,Corrin synthesis ,Inorganic Chemistry ,chemistry.chemical_compound ,Cycloisomerization ,Drug Discovery ,Physical and Theoretical Chemistry ,Contraction method - Published
- 2015
16. Synthesis of Substituted 1-Thiocyanatobutadienes and their Application in a Diels-Alder /[3,3] Sigmatropic Rearrangement Tandem Reaction
- Author
-
Sebastien Lanaspeze and Reinhard Neier
- Subjects
Ibogamine ,Cyclohexene ,Total synthesis ,General Medicine ,General Chemistry ,Sigmatropic reaction ,chemistry.chemical_compound ,chemistry ,Cascade reaction ,Diels alder ,Organic chemistry ,Enantiomer ,Enone ,Retrosynthetic analysis - Abstract
Summary.: The retrosynthetic analysis of Ibogamine, a natural psychotropic alkaloid with exceptional anti-addictive properties found in both enantiomeric forms, requires an efficient access to a racemic cyclohexene. This cyclohexene can be obtained via the sequence Diels-Alder/[3,3] sigmatropic rearrangement reaction starting from substituted 1-thiocyanatobutadienes. An efficient synthesis of the enone, a stable precursor of 1-thiocyanatobutadienes, is reported. Enolisation of this enone was studied to find the optimal conditions to get the desired 1-thiocyanatobutadienes with good Z-selectivity
- Published
- 2018
17. Macrocyclisation of 2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid model compounds of nonactic acid
- Author
-
François Loiseau, Akane Hartenbach, Reinhard Neier, Jean-Mary Simone, and Carine Eng
- Subjects
chemistry.chemical_compound ,Acetic acid ,chemistry ,biology ,Furan ,Tetra ,Organic chemistry ,Nonactin ,Dehydrogenation ,General Chemistry ,biology.organism_classification - Abstract
The macrocyclisation of hydroxyethylfuranyl acetic acid and of dehydrogenated model compounds of nonactic acid was investigated to develop a facile synthesis of nonactin analogues. By applying the Yamagushi macrocyclisation to our ω-hydroxyacids, we were able to isolate a mixture of di-, tri-, tetra- and pentameric macrocycles. Graphical abstract
- Published
- 2018
18. Sexually Dimorphic Effects of Early-life Exposures to Endocrine Disruptors: Sex-specific Epigenetic Reprogramming as a Potential Mechanism
- Author
-
Carolyn F. McCabe, Luke Montrose, Olivia S. Anderson, Kari Neier, and Dana C. Dolinoy
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Health, Toxicology and Mutagenesis ,Context (language use) ,Management, Monitoring, Policy and Law ,Biology ,Endocrine Disruptors ,Bioinformatics ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,chemistry.chemical_compound ,Phenols ,Pregnancy ,Internal medicine ,medicine ,Animals ,Humans ,Epigenetics ,Benzhydryl Compounds ,Organism ,Nature and Landscape Conservation ,Public Health, Environmental and Occupational Health ,Epigenome ,DNA Methylation ,Phenotype ,030104 developmental biology ,Endocrinology ,chemistry ,Lead ,Prenatal Exposure Delayed Effects ,Female ,Animal studies ,Reprogramming ,Toxicant - Abstract
The genetic material of every organism exists within the context of regulatory networks that govern gene expression—collectively called the epigenome. Animal models and human birth cohort studies have revealed key developmental periods that are important for epigenetic programming and vulnerable to environmental insults. Thus, epigenetics represent a potential mechanism through which sexually dimorphic effects of early-life exposures such as endocrine-disrupting chemicals (EDCs) manifest. Several animal studies, and to a lesser extent human studies, have evaluated life-course sexually dimorphic health effects following developmental toxicant exposures; many fewer studies, however, have evaluated epigenetics as a mechanism mediating developmental exposures and later outcomes. To evaluate epigenetic reprogramming as a mechanistic link of sexually dimorphic early-life EDCs exposures, the following criteria should be met: (1) well-characterized exposure paradigm that includes relevant windows for developmental epigenetic reprogramming; (2) evaluation of sex-specific exposure-related epigenetic change; and (3) observation of a sexually dimorphic phenotype in either childhood, adolescence, or adulthood.
- Published
- 2017
19. Synthesis and NMR Spectroscopic Study of the Self-Aggregation of 2-Substituted Benzene-1,3,5-tricarboxamides
- Author
-
Claudio Dalvit, Reinhard Neier, Helen Stoeckli-Evans, and Christian Invernizzi
- Subjects
Hydrogen bond ,Stereochemistry ,Organic Chemistry ,Supramolecular chemistry ,Substituent ,Crystallography ,chemistry.chemical_compound ,chemistry ,Alkoxy group ,Proton NMR ,Pi interaction ,Self-assembly ,Physical and Theoretical Chemistry ,Ene reaction - Abstract
The self-assembly of N,N′,N″-trialkylbenzene-1,3,5-tricarboxamides (BTAs) 1 or of “crowded” BTAs 11 and 12 lead to supramolecular columnar-stacked structures with attractive material properties. The introduction of three alkoxy groups is reported to reinforce the self-assembly process. The influence of a single substituent introduced onto the aromatic core of BTA significantly affects the self-assembly process. The aggregation process of 2-substituted BTAs in the bulk and in solution, as studied by DSC, POM, X-ray diffraction and 1H NMR experiments, is impaired by hydrogen-bond-accepting substituents but strengthened by non-hydrogen-bond-accepting substituents.
- Published
- 2015
20. Probing the Active Site of Pseudomonas aeruginosa Porphobilinogen Synthase Using Newly Developed Inhibitors
- Author
-
M. Nentwich, Nicole Frankenberg-Dinkel, Reinhard Neier, F. Frere, Dirk W. Heinz, and S. Gacond
- Subjects
Stereochemistry ,Protein Conformation ,Crystallography, X-Ray ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,Protein structure ,Porphobilinogen ,Magnesium ,Enzyme Inhibitors ,Magnesium ion ,Pyrrole ,chemistry.chemical_classification ,Binding Sites ,biology ,Chemistry ,Porphobilinogen synthase ,Active site ,Porphobilinogen Synthase ,Lyase ,Recombinant Proteins ,Kinetics ,Enzyme ,Pseudomonas aeruginosa ,biology.protein - Abstract
Porphobilinogen synthase catalyzes the first committed step of the tetrapyrrole biosynthesis pathway. In an aldol-like condensation, two molecules of 5-aminolevulinic acid (ALA) form the first pyrrole, porphobilinogen. Newly synthesized analogues of a reaction intermediate of porphobilinogen synthase have been employed in studying the active site and the catalytic mechanism of this early enzyme of tetrapyrrole biosynthesis. This study combines structural and kinetic evaluation of the inhibition potency of these inhibitors. In addition, one of the determined protein structures provides for the first time structural evidence of a magnesium ion in the active site. From these results, we can corroborate an earlier postulated enzymatic mechanism that starts with formation of a C-C bond, linking C3 of the A-side ALA to C4 of the P-side ALA through an aldole addition. The obtained data are discussed with respect to the current literature.
- Published
- 2017
21. Synthetic Strategies for the Synthesis and Transformation of Substituted Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues
- Author
-
Ana-Maria Buciumas, Antonia Neels, Inga Kholod, Olivier Vallat, and Reinhard Neier
- Subjects
chemistry.chemical_compound ,chemistry ,Aldol reaction ,Stereochemistry ,Organic Chemistry ,Acetal ,Ketene ,Staudinger reaction ,Physical and Theoretical Chemistry ,Ring (chemistry) ,Rhazinilam ,Pyrrole ,Acetophenone - Abstract
The biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal, variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting a suitably substituted acetophenone with O-methyl O-trimethylsilyl ketene acetal gave pyrrolinones 8a and 8b in good to excellent yields. These intermediates could be transformed in four high-yielding steps into the pyrrolic precursors 7a–c containing all the atoms necessary for the construction of rings A, B, and C of rhazinilam. Our studies illustrate a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.
- Published
- 2014
22. Preparation of precursors for the synthesis of analogues of rhazinilam
- Author
-
Olivier Vallat, Ana-Maria Buciumas, Reinhard Neier, and Inga Kholod
- Subjects
lcsh:QD241-441 ,chemistry.chemical_compound ,Natural product ,lcsh:Organic chemistry ,chemistry ,Aldol reaction ,Organic Chemistry ,Side chain ,Staudinger reaction ,Combinatorial chemistry ,Rhazinilam - Abstract
Rhazinilam a structurally relatively simple tetracyclic natural product exerts interesting anticancer activities in vitro, which are difficult to reproduce in vivo. Based on the findings accumulated during the synthetic efforts and on the known metabolic sensitivity towards oxidation and acids a modified structural analogue of rhazinilam is proposed. A novel convergent approach towards the heterocyclic biaryl unit is described. The key sequence for the construction of 7 is the Mukaiyama crossed aldol reaction followed by the Staudinger reaction. Using known N-alkylation procedures the introduction of the side chains onto the 3-pyrrolin-2one intermediate 2 needed for the construction of the tetracycle could not be achieved.
- Published
- 2014
23. Synthesis of α,β′- and β,β′-Linked Dimethoxycarbonyldipyrromethanes by Rothemund-Type Condensation
- Author
-
Helen Stoeckli-Evans, Guillaume Journot, and Reinhard Neier
- Subjects
Reaction conditions ,chemistry.chemical_compound ,Hydrogen bond ,Chemistry ,Stereochemistry ,Organic Chemistry ,Condensation ,Acetone ,Regioselectivity - Abstract
The Rothemund-type condensation of methoxycarbonylpyrrole with acetone produces mainly the α,β′-linked dipyrromethane, a building block for the synthesis of N-confused macrocycles. The influence of the reaction conditions on the regioselectivity of the process is reported. The X-ray structures of the α,α′-, α,β′- and β,β′-linked dipyrromethanes show an interesting discrimination of the structurally different types of hydrogen bonds.
- Published
- 2012
24. Synthesis and Reactions of 2-[1-Methyl-1-(pyrrolidin-2-yl)ethyl]-1H-pyrrole and Some Derivatives with Aldehydes: Chiral Structures Combining a Secondary-Amine Group with an 1H-Pyrrole Moiety as Excellent H-Bond Donor
- Author
-
Claudio Dalvit, Helen Stoeckli-Evans, Anca Pordea, and Reinhard Neier
- Subjects
Organic Chemistry ,Iminium ,Ring (chemistry) ,Biochemistry ,Medicinal chemistry ,Catalysis ,Pyrrolidine ,Cinnamaldehyde ,Inorganic Chemistry ,chemistry.chemical_compound ,Nucleophile ,chemistry ,Drug Discovery ,Organic chemistry ,Moiety ,Amine gas treating ,Physical and Theoretical Chemistry ,Pyrrole - Abstract
The synthesis of compound 2 and its derivatives 6 and 8 combining a pyrrolidine ring with an 1H-pyrrole unit is described (Scheme 2). Their attempted usability as organocatalysts was not successful. Reacting these simple pyrrolidine derivatives with cinnamaldehyde led to the tricyclic products 3b, 9b, and 10b first (Scheme 1, Fig. 2). The final, major products were the pyrrolo-indolizidine tricycles 3a, 9a, and 10a obtained via the iminium ion reacting intramolecularly with the nucleophilic β-position of the 1H-pyrrole moiety (cf. Scheme 1).
- Published
- 2012
25. Characterization of Formaldehyde Exposure Resulting from the Use of Four Professional Hair Straightening Products
- Author
-
R. E. Adams, K. Neier, L. J. Spicer, Brent L. Finley, Jennifer S. Pierce, M. E. Glynn, Shannon H. Gaffney, and A. Abelmann
- Subjects
Time Factors ,Chemistry ,Air exchange ,Hair Preparations ,Public Health, Environmental and Occupational Health ,Formaldehyde ,Air Pollutants, Occupational ,Barbering ,Ventilation ,Hair treatment ,chemistry.chemical_compound ,Animal science ,Air pollutants ,Limit of Detection ,Air Pollution, Indoor ,Occupational Exposure ,Bulk samples ,Humans ,Occupational exposure ,Hair straightening ,FORMALDEHYDE EXPOSURE - Abstract
An exposure simulation study was conducted to characterize potential formaldehyde exposures of salon workers and clients during keratin hair smoothing treatments. Four different hair treatment brands (Brazilian Blowout, Coppola, Global Keratin, and La Brasiliana) were applied to separate human hair wigs mounted on mannequin heads. Short-term (6-16 min) and long-term (41-371 min) personal and area samples (at distances of 0.5 to 3.0 m from the source) were collected during each treatment for the 1-day simulation. A total of 88 personal, area, and clearance samples were collected. Results were analyzed based on task sampling (blow-dry, flat-iron), treatment sampling (per hair product), and time-weighted averages (per hair treatment, four consecutive treatments). Real-time monitoring of tracer gas levels, for determining the air exchange rate, and formaldehyde levels were logged throughout the simulation. Bulk samples of each hair treatment were collected to identify and quantify formaldehyde and other chemical components that may degrade to formaldehyde under excessive heat. Mean airborne concentrations of formaldehyde ranged from 0.08-3.47 ppm during blow-dry and 0.08-1.05 ppm during flat-iron. During each treatment, the mean airborne concentrations ranged from 0.02-1.19 ppm throughout different zones of the salon. Estimated 8-hr time-weighted averages for one treatment per day ranged from 0.02 ppm for La Brasiliana to 0.08-0.16 ppm for Brazilian Blowout. For four treatments per day, means ranged from 0.04-0.05 ppm for La Brasiliana to 0.44-0.75 ppm for Brazilian Blowout. Using all four products in one day resulted in estimated 8-hr time-weighted averages ranging from 0.17-0.29 ppm. Results from bulk sampling reported formaldehyde concentrations of 11.5% in Brazilian Blowout, 8.3% in Global Keratin, 3% in Coppola, and 0% in La Brasiliana. Other products that degrade into formaldehyde were detected in Global Keratin, Coppola, and La Brasiliana. The results of this study show that professional hair smoothing treatments--even those labeled "formaldehyde-free"--have the potential to produce formaldehyde concentrations that meet or exceed current occupational exposure limits.
- Published
- 2011
26. Click Chemistry Applied in the Synthesis of Symmetrical Triphenylene-Based Discotic Liquid-Crystalline Dimers
- Author
-
Reinhard Neier and Damien Thevenet
- Subjects
chemistry.chemical_compound ,Chemistry ,Organic Chemistry ,Polymer chemistry ,Click chemistry ,Triphenylene ,Columnar phase ,Photochemistry ,Catalysis - Published
- 2011
27. Thione Esters as Substrates for the Stereoselective Alkylation of Model Compounds of Nonactic Acids
- Author
-
Reinhard Neier, François Loiseau, and Inga Kholod
- Subjects
Allyl iodide ,Organic Chemistry ,Nonactin ,Alkylation ,Medicinal chemistry ,Cis trans isomerization ,chemistry.chemical_compound ,chemistry ,Heck reaction ,Michael reaction ,Organic chemistry ,Physical and Theoretical Chemistry ,Tetrahydrofuran ,Cis–trans isomerism - Abstract
The naturally occurring macrotetrolide antibiotic nonactin is used in ammonium ion selective electrodes. To increase the lifetime of nonactin in the semipermeable membrane of these sensors we have developed methods for the introduction of hydrophobic side-chains. Simple model compounds for nonactic acid such as 5 and 7 were synthesised. Maintaining the cis arrangement of the substituents in the 2,5-disubstituted tetrahydrofurans proved to be difficult. Three different routes were studied. The enolates obtained by treatment with NaHMDS or KHMDS could be alkylated with benzyl or allyl iodide as electrophiles. Under these conditions a cis/trans isomerisation of the substituents on the tetrahydrofuran ring occurred. A multistep methodology was developed as a synthetic alternative. The sequence consisted of a selective retro-Michael reaction, a 5-exo-tet iodocyclisation and a radical substitution. The products obtained by the two methodologies could be correlated, and thereby a tentative assignment of the relative configurations could be achieved. In the third route the thione ester 18 was deprotonated with tBuOK. At temperatures below -78 °C, the enolate maintained the cis configuration of the substituents at the tetrahydrofuran ring. The alkylated product 12 could be isolated with a satisfactory cis/trans ratio of 85:15. The model compound 12 could be successfully transformed into more hydrophobic derivatives by using either the Heck coupling or the cross-coupling metathesis transformation.
- Published
- 2010
28. Health Related Quality of Life and Fatigue Improve on Second Line Treatments in Pediatric Immune Thrombocytopenia (ITP)
- Author
-
James B. Bussel, Carolyn M. Bennett, Vicky R. Breakey, Kristina M. Haley, Ellis J. Neufeld, Rachael F. Grace, Jenny M. Despotovic, George R. Buchanan, Amy E. Geddis, Robert J. Klaassen, Rukhmi Bhat, Michael Jeng, Peter W. Forbes, Kristin A. Shimano, Cindy Neunert, Kerry Hege, Jennifer A. Rothman, Shelley E. Crary, Melissa J. Rose, Michele P. Lambert, Michelle Neier, Yves D. Pastore, Nolan Neu, and Adonis Lorenzano
- Subjects
Health related quality of life ,Pediatrics ,medicine.medical_specialty ,Romiplostim ,business.industry ,medicine.medical_treatment ,Immunology ,Splenectomy ,Eltrombopag ,Cell Biology ,Hematology ,030204 cardiovascular system & hematology ,Dapsone ,Biochemistry ,Rho(D) immune globulin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Second line ,chemistry ,medicine ,Rituximab ,business ,030215 immunology ,medicine.drug - Abstract
Background: The impact of second line therapies on health related quality of life (HRQoL) and fatigue in pediatric patients with ITP is not well studied. Objective: To describe the impact of second line therapies on HRQoL and fatigue in North American pediatric patients with ITP. Methods: A longitudinal observational cohort of 120 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, corticosteroids or anti-D immunoglobulin) as monotherapy. HRQoL (Kids ITP Tool - KIT) and fatigue (Hockenberry Fatigue Scale - FS) surveys were completed prior to starting treatment (baseline) and 1 and 12 months after starting treatment by patient/caregiver. KIT is scored from 0 (worst) to 100 (best), and the FS scores were re-scaled so that 0 is no fatigue and 100 is highest fatigue. At the same time points as the patient/caregiver surveys, physicians assessed the perceived effect of treatment on patient HRQoL using a 7-point scale. ANOVA was used to compare the baseline means of the treatment groups. This study specifically compared change from baseline to 1 month in the KIT and FS using paired t-tests within each treatment group. The 12 month timepoint was not used in the paired analysis of individual treatments due to attrition between 1 and 12 months. Results: The median age at enrollment was 11.3 y (1.2-17.8), and 16% (19/120) had newly diagnosed ITP, 31% (37/120) had persistent ITP, and 53% (64/120) had chronic ITP. The median number of prior treatments was 3 (range: 1-9). Fifty-eight (48%) patients had received at least one prior second line treatment. Treatments selected for second line treatment included: rituximab (n=43), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=19), splenectomy (n=4), and dapsone (n=3). The child and parent proxy KIT scores significantly improved on rituximab (p As previously described, at enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 45%, moderately in 38%, and almost not at all in 3%. Physicians reported that HRQoL improved in 68% (range: 64-75%) of patients while on treatment from baseline to 1 month with no significant difference by treatment group (p=0.46). The physician's assessment of the patient's baseline HRQoL significantly correlated with the child and parent proxy KIT report (p At enrollment, the median FS-Child score (n=54) was 18.5 (range 0-85), the median FS-Adolescent score (n=42) was 20.2 (0-73), and the median FS-Parent (n= 100) score was 35 (7-81). One month FS-Child improved for those who were treated with rituximab (p=0.03); there was no significant change in fatigue on the other treatments. One month FS-Parent significantly improved for those treated with rituximab (p=0.015) and eltrombopag (p=0.009). Conclusions: In this pediatric cohort, all second line treatments appear to significantly improve HRQoL in ITP. Rituximab had the greatest impact in decreasing fatigue at one month. Physician assessment of patient HRQoL did not correlate well with patient assessment after treatment was started, suggesting there may be challenges in ascertaining the effect of treatment on HRQoL. Future analysis of ICON1 will consider the impact of treatment on HRQoL and fatigue while also accounting for the treatment effect on bleeding and platelet count. Disclosures Grace: Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klaassen: Amgen: Consultancy; Hoffman-La Roche LTD: Consultancy; Octapharma: Honoraria; Baxalta: Honoraria; Biogen Canada LTD: Consultancy; Agios Pharmaceuticals: Consultancy. Despotovic: Sanofi: Consultancy; Schell Cooley LLP: Other: Expert witness. Bussel: Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rothman: Pfizer: Consultancy; Agios Pharmaceuticals: Honoraria. Haley: Genentech: Honoraria; Baxalta: Honoraria; CSL Behring: Honoraria. Neufeld: Octapharma: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lambert: Educational Concepts in Medicine: Honoraria; Novartis: Honoraria; AstraZeneca: Research Funding.
- Published
- 2017
29. Novel Bioconjugates of Aminolevulinic Acid with Nucleosides
- Author
-
Ramakrishnan Vallinayagam, Lucienne Juillerat-Jeanneret, Julien Furrer, Frédéric Schmitt, Reinhard Neier, and Patrice Gurba
- Subjects
chemistry.chemical_classification ,Protoporphyrin IX ,Organic Chemistry ,Cell ,Cancer therapy ,Prodrug ,Adenosine ,Catalysis ,Amino acid ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Biochemistry ,medicine ,Thymidine ,medicine.drug ,Conjugate - Abstract
Esters and amino acid derivatives of 5-aminolevulinic acid (ALA)are efficient prodrugs for the production of protoporphyrin IX (PpIX),which has been used in photodynamic cancer therapy (PDT). The synthesisof novel bioconjugates combining ALA with adenosine and thymidineis reported. The novel bioconjugates have been made using a robustmethodology. The new class of prodrugs contains one, two, or threeALA per molecule. Preliminary cell tests in human cancer cell linesindicate that the thymidine conjugate of ALA is an efficient prodrugfor PDT.
- Published
- 2008
30. Facile Synthesis of a 'Ready to Use' Precursor of Porphobilinogen and Its Amino Acid Derivatives
- Author
-
Carole Pissot Soldermann, Reinhard Neier, Ramakrishnan Vallinayagam, and Manuel Tzouros
- Subjects
chemistry.chemical_classification ,congenital, hereditary, and neonatal diseases and abnormalities ,Molecular Structure ,Porphobilinogen ,Organic Chemistry ,nutritional and metabolic diseases ,Stereoisomerism ,Combinatorial chemistry ,Chemical synthesis ,Amino acid ,chemistry.chemical_compound ,chemistry ,Aldol reaction ,Enzymatic hydrolysis ,Yield (chemistry) ,Levulinic acid ,Aldol condensation ,Amino Acids ,skin and connective tissue diseases - Abstract
A practical synthesis of porphobilinogen based on the biosynthetic mechanism is described. The crossed Mukayiama aldol reaction is the key step creating the central carbon-carbon bond between the two protected forms of 5-aminolevulinic acids. The optimized sequence gives a crystalline, storable precursor, which can be transformed in high yield into porphobilinogen and bioconjugates thereof. The enzymatic hydrolysis of the precursor produces porphobilinogen in quantitative yield.
- Published
- 2007
31. Synthesis of Novel and Stable 5-Aminolevulinic Acid Derivatives for the Efficient Synthesis of 5-Aminolevulinic Acid Based Prodrugs
- Author
-
Reinhard Neier, Hugo Bertschy, Yann Berger, Virginie Wenger, and Ramakrishnan Vallinayagam
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,Chemical transformation ,chemistry ,Organic Chemistry ,Organic chemistry ,Prodrug ,Protecting group ,Porphyrin ,Catalysis ,Amino acid - Abstract
The efficient synthesis of two stable, easily handled precursors of 5-aminolevulinate is reported. These precursors are stable to the chemical transformation needed for the synthesis of bioconjugates and can be readily deprotected in good yields.
- Published
- 2007
32. The High Stereoselectivity of the Tandem Sequence Diels-Alder Reaction/Ireland-Claisen Rearrangement Starting from Substituted O-(E)-Buta-1,3-dienyl Ketene Acetals and Cyclic Dienophiles
- Author
-
Nicolas Soldermann, Antonia Neels, Joerg Velker, Reinhard Neier, and Helen Stoeckli-Evans
- Subjects
Bicyclic molecule ,Chemistry ,Stereochemistry ,fungi ,Organic Chemistry ,Cyclohexene ,Ketene ,Sigmatropic reaction ,Catalysis ,Cycloaddition ,chemistry.chemical_compound ,Cascade reaction ,Ireland–Claisen rearrangement ,Diels–Alder reaction - Abstract
A new tandem reaction leads to bicyclic cyclohexene derivatives with complete control of the relative configuration of the four chiral centers formed. The high diastereoselectivity is the consequence of an endo-selective Diels-Alder reaction followed by an Ireland-Claisen rearrangement that proceeds via a boat-like transition state. © Georg Thieme Verlag Stuttgart.
- Published
- 2007
33. Synthesis of Bisubstrate Inhibitors of Porphobilinogen Synthase fromPseudomonas aeruginosa
- Author
-
F. Frere, S. Gacond, Jean-Philippe Faurite, Reinhard Neier, M. Nentwich, and Nicole Frankenberg-Dinkel
- Subjects
Stereochemistry ,Bioengineering ,medicine.disease_cause ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Porphobilinogen ,medicine ,Levulinic acid ,Molecule ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,biology ,Pseudomonas aeruginosa ,Porphobilinogen synthase ,Active site ,Porphobilinogen Synthase ,General Chemistry ,General Medicine ,Enzyme ,chemistry ,Functional group ,biology.protein ,Molecular Medicine - Abstract
Porphobilinogen synthase (PBGS) synthesizes porphobilinogen 2 (PBG), the common precursor of all natural tetrapyrroles, through an asymmetric condensation of two molecules of 5-aminolevulinic acid 1 (ALA). Symmetrically linked dimers 7-11 derived from levulinic acid 3 (gamma-oxovaleric acid) have been synthesized to mimic the assumed bisubstrate bound to the active site of the enzyme. Their inhibition potential was characterized by determination of the IC(50) and K(i) values using PBGS from Pseudomonas aeruginosa. The polarity and the size of the functional group linking the two levulinic acid 3 units have a strong influence on the inhibition behavior.
- Published
- 2007
34. Malonylation/Decarbalkoxylation of Furan Derivatives as Key Steps for the Preparation of Nonactic Acid Derivatives. Part I [1]
- Author
-
François Loiseau, Julie Jeanneret-Gris, Pavel Bobal, David Carcache, Jean-Mary Simone, and Reinhard Neier
- Subjects
chemistry.chemical_compound ,chemistry ,Furan ,Organic chemistry ,General Chemistry - Abstract
Summary.: A malonylation/decarbalkoxylation sequence from 2-substituted furans was investigated in view of developing a scalable synthesis of hydrophobic nonactic acid analogues
- Published
- 2007
35. ChemInform Abstract: Synthetic Strategies for the Synthesis and Transformation of Substituted Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues
- Author
-
Antonia Neels, Olivier Vallat, Reinhard Neier, Ana-Maria Buciumas, and Inga Kholod
- Subjects
chemistry.chemical_compound ,chemistry ,General Medicine ,Combinatorial chemistry ,Rhazinilam ,Pyrrole derivatives ,Transformation (music) - Abstract
Studies on the preparation of pyrrolinone-based analogs of rhazinilam (VII) are presented, using suitably functionalized pyrrolinones, e.g. (VI), as key building blocks.
- Published
- 2015
36. Catalytic Hydrogenation of meso-Octamethylporphyrinogen (Calix[4]pyrrole)
- Author
-
Helen Stoeckli-Evans, Reinhard Neier, Andrea Gualandi, Christophe Letondor, Diego Savoia, Guillaume Journot, G. Journot, C. Letondor, R. Neier, H. Stoeckli-Evan, D. Savoia, and A. Gualandi
- Subjects
Models, Molecular ,Porphyrins ,Pyrrolidines ,Heterogeneous catalysis ,Catalysis ,Pyrrolidine ,chemistry.chemical_compound ,PORPHYRINOIDS ,Organic chemistry ,Pyrroles ,NITROGEN HETEROCYCLES ,Catalytic hydrogenation ,Pyrrole ,Molecular Structure ,Organic Chemistry ,Diastereomer ,Substrate (chemistry) ,Stereoisomerism ,General Chemistry ,CALIX[4]PYRROLE ,Solubility ,chemistry ,Solvents ,Hydrogenation ,Calixarenes - Abstract
Hydrogenation of meso-octamethylporphyrinogen (calix[4]pyrrole) with a number of heterogeneous catalysts under different experimental conditions has been investigated. GC-MS analyses of the reaction mixtures showed the formation of one to four products in low to moderate yields: three of them were diastereoisomers of the product derived from half-hydrogenation of the substrate, and displayed alternating pyrrolidine and pyrrole rings, while the fourth was the all-cis saturated product. An acidic medium was necessary to achieve hydrogenation. However, the use of too strongly acidic solvents or additives was detrimental to the stability of the substrate and/or the catalyst.
- Published
- 2010
37. Phase-transformation-induced twinning of an iron(III) calix[4]pyrrolidine complex
- Author
-
Reinhard Neier, Guillaume Journot, and Helen Stoeckli-Evans
- Subjects
Coordination sphere ,Hydrogen bond ,Chemistry ,Crystal structure ,Triclinic crystal system ,Condensed Matter Physics ,Pyrrolidine ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Materials Chemistry ,Macrocyclic ligand ,Physical and Theoretical Chemistry ,Crystal twinning ,Monoclinic crystal system - Abstract
The title compound, tetrachlorido-1κCl;2κ3Cl-(2,2,7,7,12,12,17,17-octamethyl-21,22,23,24-tetraazapentacyclo[16.2.1.13,6.18,11.113,16]tetracosane-1κ4N,N′,N′′,N′′′)-μ2-oxido-diiron(III), [Fe2Cl4O(C28H52N4)], undergoes a slow phase transformation atca173 K from monoclinic space groupP21/n, denoted form (I), to the maximal non-isomorphic subgroup, triclinic space groupP\overline{1}, denoted form (II), which is accompanied by nonmerohedral twinning [twin fractions of 0.693 (4) and 0.307 (4)]. The transformation was found to be reversible, as on raising the temperature the crystal reverted to monoclinic form (I). In the asymmetric unit of form (I),Z′ = 1, while in form (II),Z′ = 2, with a very small reduction (ca1.8%) in the unit-cell volume. The two independent molecules (AandB) in form (II) are related by a pseudo-twofold screw axis along thebaxis. The molecular overlay of moleculeAon moleculeBhas an r.m.s. deviation of 0.353 Å, with the largest distance between two equivalent atoms being 1.202 Å. The reaction of calix[4]pyrrolidine, the fully reduced form ofmeso-octamethylporphyrinogen, with FeCl3gave a red–brown solid that was recrystallized from ethanol in air, resulting in the formation of the title compound. In both forms, (I) and (II), the FeIIIatoms are coordinated to the macrocyclic ligand and have distorted octahedral FeN4OCl coordination spheres. These FeIIIatoms lie out of the mean plane of the four N atoms, displaced towards the O atom of the [OFeCl3] unit by 0.2265 (5) Å in form (I), and by 0.2210 (14) and 0.2089 (14) Å, respectively, in the two independent molecules (AandB) of form (II). The geometry of the [OFeCl3] units are similar, with each FeIIIatom having a tetrahedral coordination sphere. The NH H atoms are directed below the planes of the macrocycles and are hydrogen bonded to the coordinated Cl−ions. There are also intramolecular C—H...Cl hydrogen bonds present in both (I) and (II). In form (I), there are no significant intermolecular interactions present. In form (II), the individual molecules are arranged in alternate layers parallel to theacplane. TheBmolecules are linked by a C—H...Cl hydrogen bond, forming chains along [100].
- Published
- 2014
38. The X-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with two diacid inhibitors
- Author
-
Leighton Coates, Peter M. Shoolingin-Jordan, Martin J. Warren, Amanda A. Brindley, Reinhard Neier, Jonathan B. Cooper, Richard J. Newbold, Frédéric Stauffer, Steve P. Wood, and Peter T. Erskine
- Subjects
Models, Molecular ,Macromolecular Substances ,Protein Conformation ,Stereochemistry ,Static Electricity ,Biophysics ,Saccharomyces cerevisiae ,Crystallography, X-Ray ,Biochemistry ,Substrate Specificity ,Catalysis ,chemistry.chemical_compound ,Protein structure ,4-Oxosebacic acid ,Biosynthesis ,Structural Biology ,Catalytic Domain ,Genetics ,Enzyme Inhibitors ,Molecular Biology ,Schiff Bases ,chemistry.chemical_classification ,4,7-Dioxosebacic acid ,Schiff base ,biology ,Chemistry ,Substrate (chemistry) ,Active site ,Porphobilinogen Synthase ,5-Aminolevulinate dehydratase ,Cell Biology ,Enzyme ,Dehydratase ,biology.protein ,Mechanism ,Decanoic Acids - Abstract
The structures of 5-aminolaevulinic acid dehydratase complexed with two irreversible inhibitors (4-oxosebacic acid and 4,7-dioxosebacic acid) have been solved at high resolution. Both inhibitors bind by forming a Schiff base link with Lys 263 at the active site. Previous inhibitor binding studies have defined the interactions made by only one of the two substrate moieties (P-side substrate) which bind to the enzyme during catalysis. The structures reported here provide an improved definition of the interactions made by both of the substrate molecules (A- and P-side substrates). The most intriguing result is the novel finding that 4,7-dioxosebacic acid forms a second Schiff base with the enzyme involving Lys 210. It has been known for many years that P-side substrate forms a Schiff base (with Lys 263) but until now there has been no evidence that binding of A-side substrate involves formation of a Schiff base with the enzyme. A catalytic mechanism involving substrate linked to the enzyme through Schiff bases at both the A- and P-sites is proposed.
- Published
- 2001
39. Mechanistic Basis for Suicide Inactivation of Porphobilinogen Synthase by 4,7-Dioxosebacic Acid, an Inhibitor That Shows Dramatic Species Selectivity
- Author
-
Jukka Kervinen, Alexander Zdanov, and Alexander Wlodawer, Reinhard Neier, Eileen K. Jaffe, and Frédéric Stauffer
- Subjects
Cations, Divalent ,Stereochemistry ,Dimer ,Molecular Sequence Data ,Lysine ,Crystallography, X-Ray ,Biochemistry ,Cofactor ,Substrate Specificity ,chemistry.chemical_compound ,Species Specificity ,Escherichia coli ,Humans ,Magnesium ,Amino Acid Sequence ,Enzyme Inhibitors ,Heme ,Schiff Bases ,Binding Sites ,Schiff base ,biology ,Chemistry ,Porphobilinogen synthase ,Porphobilinogen Synthase ,Lyase ,Tetrapyrrole ,Enzyme Activation ,Kinetics ,Zinc ,Mutagenesis, Site-Directed ,biology.protein ,Crystallization ,Decanoic Acids - Abstract
4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible inhibitor of porphobilinogen synthase (PBGS). PBGS catalyzes the first common step in the biosynthesis of the tetrapyrrole cofactors such as heme, vitamin B(12), and chlorophyll. 4,7-DOSA was designed as an analogue of a proposed reaction intermediate in the physiological PBGS-catalyzed condensation of two molecules of 5-aminolevulinic acid. As shown here, 4,7-DOSA exhibits time-dependent and dramatic species-specific inhibition of PBGS enzymes. IC(50) values vary from 1 microM to 2.4 mM for human, Escherichia coli, Bradyrhizobium japonicum, Pseudomonas aeruginosa, and pea enzymes. Those PBGS utilizing a catalytic Zn(2+) are more sensitive to 4,7-DOSA than those that do not. Weak inhibition of a human mutant PBGS establishes that the inactivation by 4,7-DOSA requires formation of a Schiff base to a lysine that normally forms a Schiff base intermediate to one substrate molecule. A 1.9 A resolution crystal structure of E. coli PBGS complexed with 4,7-DOSA (PDB code ) shows one dimer per asymmetric unit and reveals that the inhibitor forms two Schiff base linkages with each monomer, one to the normal Schiff base-forming Lys-246 and the other to a universally conserved "perturbing" Lys-194 (E. coli numbering). This is the first structure to show inhibitor binding at the second of two substrate-binding sites.
- Published
- 2001
40. Inhibition Studies of Porphobilinogen Synthase fromEscherichia coli Differentiating between the Two Recognition Sites
- Author
-
Jean-Philippe Faurite, Frédéric Stauffer, Caroline Engeloch-Jarret, Reinhard Neier, Janette Bobalova, and Eleonora Zizzari
- Subjects
biology ,Stereochemistry ,Porphobilinogen synthase ,Organic Chemistry ,Substrate (chemistry) ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,A-site ,chemistry ,Biosynthesis ,Porphobilinogen ,biology.protein ,medicine ,Molecular Medicine ,P-site ,Binding site ,Molecular Biology ,Escherichia coli - Abstract
Porphobilinogen synthase condenses two molecules of 5-aminolevulinate in an asymmetric way. This unusual transformation requires a selective recognition and differentiation between the substrates ending up in the A site or in the P site of porphobilinogen synthase. Studies of inhibitors based on the key intermediate first postulated by Jordan allowed differentiation of the two recognition sites. The P site, whose structure is known from X-ray crystallographic studies, tolerates ester functions well. The A site interacts very strongly with nitro groups, but is not very tolerant to ester functions. This differentiation is a central factor in the asymmetric handling of the two identical substrates. Finally, it could be shown that the keto group of the substrate bound at the A site is not only essential for the recognition, but that an increase in electrophilicity of the carbon atom also increases the inhibition potency considerably. This has important consequences for the recognition process at the A site, whose exact structure is not yet known.
- Published
- 2001
41. Ethylene Glycol and Amino Acid Derivatives of 5-Aminolevulinic Acid as New Photosensitizing Precursors of Protoporphyrin IX in Cells
- Author
-
Lucienne Juillerat-Jeanneret, Olivier Siri, Alain Greppi, Reinhard Neier, and Yann Berger
- Subjects
medicine.medical_treatment ,Protoporphyrins ,Photodynamic therapy ,Glutamyl Aminopeptidase ,Aminopeptidases ,Fluorescence ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Amino Acids ,Protein Precursors ,Cytotoxicity ,chemistry.chemical_classification ,Photosensitizing Agents ,Dipeptide ,Protoporphyrin IX ,Aminolevulinic Acid ,Dipeptides ,Photosensitizing Agent ,Rats ,Amino acid ,chemistry ,Biochemistry ,Molecular Medicine ,Ethylene Glycols ,Protoporphyrin ,Ethylene glycol - Abstract
Protoporphyrin IX (PpIX) is used as a photosensitizing agent in photodynamic detection and therapy (PDT) of cancer and is synthesized intracellularly from aminolevulinic acid (ALA) precursors. To evaluate means to specifically target ALA derivatives to defined cells, we have synthesized and characterized ethylene glycol esters and amino acid pseudodipeptide derivatives of ALA as potential specific substrates for cellular esterases and aminopeptidases, respectively. The PpIX formation induced by these products was investigated using cultures of human and rat cell lines of carcinoma and endothelial origins. The cytotoxicity of these compounds in the absence of light was also controlled. The results have shown that ethylenglycol esters can induce high levels of PpIX and are useful at concentrations below their cytotoxicity threshold. From the ALA-amino acid derivatives which were evaluated, the highest PpIX production was obtained using ALA derivatives of neutral amino acids, as compared to acidic or basic amino acids.
- Published
- 2000
42. [Untitled]
- Author
-
Jean-Mary Simone, Reinhard Neier, Thomas Thyrann, and Klaus Neuschütz
- Subjects
Tandem ,Organic Chemistry ,Ketene ,Biochemistry ,Propanamide ,Medicinal chemistry ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,Electron transfer ,chemistry ,Polymerization ,Yield (chemistry) ,Drug Discovery ,Reactivity (chemistry) ,Physical and Theoretical Chemistry - Abstract
We report the synthesis of N-benzyl-N-[(E)-buta-1,3-dienyl]propanamide (6) and its corresponding O-silyl-substituted ketene N,O-acetal 7 and their Diels-Alder reaction. Propanamide 6 reacted smoothly, whereas the yield obtained from 7 was low, probably due to polymerization of the dienophile induced by electron transfer. The ketene N,O-acetals 27a – g were synthesized starting from the corresponding benzamides 25a – e (Scheme 9). The ketene N,O-acetals 27a – g showed increased stabilities and underwent amino-Claisen rearrangements under thermal conditions. Using catalysts, interesting side reactions leading either to the annulated systems rac-35 – 37 or to a β-lactam rac-34 were observed.
- Published
- 2000
43. Application of the Novel Tandem Process Diels-Alder Reaction/Ireland-Claisen Rearrangement to the Synthesis of rac-Juvabione and rac-Epijuvabione
- Author
-
Helen Stoeckli-Evans, Joerg Velker, Olivier Vallat, Reinhard Neier, and Nicolas Soldermann
- Subjects
Tandem ,fungi ,Organic Chemistry ,Biochemistry ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Scientific method ,Drug Discovery ,Organic chemistry ,Physical and Theoretical Chemistry ,Juvabione ,Ireland–Claisen rearrangement ,Diels–Alder reaction - Abstract
The novel tandem process Diels-Alder reaction/Ireland-Claisen rearrangement shows a high diastereoselectivity for the Ireland-Claisen rearrangement starting from the endo-product of the Diels-Alder reaction. Based on this mechanistic knowledge, the novel tandem process could be applied to the synthesis of rac-juvabione.
- Published
- 2000
44. Inhibition of Escherichia coli porphobilinogen synthase using analogs of postulated intermediates
- Author
-
Rainer Martin Lüönd, Peter Schürmann, Caroline Jarret, Maurus Marty, Janette Bobalova, Reinhard Neier, Matthias E. Henz, and Frédéric Stauffer
- Subjects
Stereochemistry ,Porphobilinogen ,Clinical Biochemistry ,Substrate analog ,Binding, Competitive ,Biochemistry ,Substrate Specificity ,Structure-Activity Relationship ,chemistry.chemical_compound ,Biosynthesis ,Catalytic Domain ,Inhibition studies ,Drug Discovery ,Escherichia coli ,Dicarboxylic Acids ,Enzyme Inhibitors ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,biology ,Porphobilinogen synthase ,Substrate (chemistry) ,Active site ,Iminium ,Aminolevulinic Acid ,General Medicine ,Kinetics ,Analogs of intermediates ,Enzyme ,Models, Chemical ,chemistry ,biology.protein ,Molecular Medicine - Abstract
Background: Porphobilinogen synthase is the second enzyme involved in the biosynthesis of natural tetrapyrrolic compounds, and condenses two molecules of 5-aminolevulinic acid (ALA) through a nonsymmetrical pathway to form porphobilinogen. Each substrate is recognized individually at two different active site positions to be regioselectively introduced into the product. According to pulse-labeling experiments, the substrate forming the propionic acid sidechain of porphobilinogen is recognized first. Two different mechanisms for the first bond-forming step between the two substrates have been proposed. The first involves carbon–carbon bond formation (an aldol-type reaction) and the second carbon–nitrogen bond formation, leading to an iminium ion. Results: With the help of kinetic studies, we determined the Michaelis constants for each substrate recognition site. These results explain the Michaelis–Menten behavior of substrate analog inhibitors — they act as competitive inhibitors. Under standard conditions, however, another set of inhibitors demonstrates uncompetitive, mixed, pure irreversible, slow-binding or even quasi-irreversible inhibition behavior. Conclusions: Analysis of the different classes of inhibition behavior allowed us to make a correlation between the type of inhibition and a specific site of interaction. Analyzing the inhibition behavior of analogs of postulated intermediates strongly suggests that carbon–nitrogen bond formation occurs first.
- Published
- 2000
45. Influence of the nature and substitution of chiral 2,3-epoxy alcohol derivatives on the enantiomeric elution order on chiralcel OD column
- Author
-
Chantal Zedde, Reinhard Neier, Michel Baltas, Kassoum Nacro, Liliane Gorrichon, and Jean-Marc Escudier
- Subjects
Pharmacology ,Elution ,Chemistry ,Organic Chemistry ,Synthon ,Enantioselective synthesis ,Epoxide ,Alcohol ,Catalysis ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Alkoxy group ,Nerol ,Organic chemistry ,Enantiomer ,Spectroscopy - Abstract
A number of 2,3-epoxy alcohol derivatives (1–16), obtained either asracemates or through the Sharpless asymmetric epoxidation reaction, were studied ona Chiralcel OD column. Nearly all compounds exhibit good enantioselective resolutionon this chiral support. The order of elution of enantiomers is reversed between nerol andgeraniol compounds. For 2,3-epoxy alcohols bearing a remote alkoxy (or silyloxy) group,the order of the enantiomeric elution alternates with the number n (n = 1–3) of methy-lenic groups present between the epoxide ring and the terminal OR (R=p−BrBn orOSitBuPh 2 ) functionality. In the case of trans 2,3-epoxy alcohols for the same number n,the order of elution is reversed when changing the terminal group −OSi to −OR. Thelatter group greatly improves the separation of the two enantiomers. KEY WORDS: 2,3-epoxyalcohols; enantiomeric elution order; protective groups; chain length influenceFor the last decade, intense interest has focused on thedevelopment of synthetic methods leading to optically ac-tive synthons possessing a 1,2, 1,3, 1,2,3 polyhydroxylatedframe.
- Published
- 1998
46. rac-(Z)-Ethyl 2-bromo-2-[(3R,5R)-3-bromo-5-methyltetrahydrofuran-2-ylidene]acetate
- Author
-
Helen Stoeckli-Evans, François Loiseau, Reinhard Neier, and Gaël Labat
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Double bond ,Stereochemistry ,Hydrogen bond ,General Medicine ,Crystal structure ,General Biochemistry, Genetics and Molecular Biology ,Tetrahydrofuran ,Methyl group - Abstract
In the title compound, C9H12Br2O3, a (tetrahydrofuran-2-ylidene)acetate, the double bond has the Z form. In the tetrahydrofuran group, the relative configuration of the Br atom in the 3-position and the methyl group in the 5-position is anti. The compound crystallizes with two independent molecules per asymmetric unit and, in the crystal structure, the individual molecules are linked to their symmetry-equivalent molecules by C—H⋯O hydrogen bonds, so forming centrosymmetric hydrogen-bonded dimers.
- Published
- 2006
47. rac-(R)-2-[(2R,5R)-5-Methyltetrahydrofuran-2-yl]propanoic acid
- Author
-
Reinhard Neier, François Loiseau, and Helen Stoeckli-Evans
- Subjects
biology ,Stereochemistry ,Hydrogen bond ,General Chemistry ,Crystal structure ,Condensed Matter Physics ,Ring (chemistry) ,biology.organism_classification ,chemistry.chemical_compound ,Propanoic acid ,chemistry ,Furan ,Tetra ,General Materials Science - Abstract
In the crystal structure of the title compound, C8H14O3, the 2,5-tetrahydrofuran ring junction is cis. The relative configuration of position 2 in the propanoic acid group was found to be the same as that in positions 2 and 5 in the tetrahydrofuran ring. In the crystal structure, symmetry-related molecules are linked by O—H⋯O hydrogen bonds to form centrosymmetric dimers.
- Published
- 2006
48. The preparation and the cascade reactions of N-butadienyl-N-alkylketeneN,O-tert-butyldimethylsilyl acetals
- Author
-
Pierre-Yves Eschler, Reinhard Neier, Manuel Tharin, and Andreas Franz
- Subjects
Acylation ,chemistry.chemical_compound ,chemistry ,Bicyclic molecule ,Cascade ,Organic Chemistry ,Drug Discovery ,Ketene ,Organic chemistry ,Biochemistry - Abstract
The preparation of N-butadienyl-N-alkylketene N,O-tert-butyldimethylsilyl acetals (11a - d)from readily available starting materials is described. The cascade Diels-Alder reaction followed by acylation of these ketene acetals yields bicyclic and tricyclic products 7.13a,b and 14c,d with high diastereoselectivity.
- Published
- 1996
49. Reduced polyoxomolybdates with the Keggin and Dawson structures: preparation and crystal structures of two-electron reduced [K(18-crown-6)]2[N(PPh3)2]2[HPMo12O40]·8MeCN·18-crown-6 and four-electron reduced [NBun4]5[H3S2Mo18O62]·4MeCn (18-crown-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane)
- Author
-
Christa Trojanowski, Ralf Neier, and Rainer Mattes
- Subjects
Bond length ,Crystallography ,chemistry.chemical_compound ,chemistry ,Octahedron ,18-Crown-6 ,Molecular orbital ,General Chemistry ,Crystal structure ,Nuclear magnetic resonance spectroscopy ,Acetonitrile ,Ion - Abstract
By reaction of [K(18-crown-6)][N(PPh3)2]2[PMo12O40]·2MeCN 1 and [NBun4]4[S2Mo18O62] with PPh3 in acetonitrile the new compounds [K(18-crown-6)]2[N(PPh3)2]2[HPMo12O40]·8MeCN·18-crown-6 2(18-crown-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane) and [NBun4]5[H3S2Mo18O62]·4MeCN 3 were prepared. Compound 2 contains the two-electron reduced [HPMo12O40]4– ion having the α-Keggin structure, 3 the four-electron reduced [H3S2Mo18O62]5– ion having the α-Dawson structure. Compounds 1–3 were characterised by means of IR and NMR spectroscopy and X-ray diffraction. The structures of 1 and 2 are disordered in space group P. The heteropolyanions show apparent Th symmetry; their actual symmetry is T. Upon reduction the Mo ⋯ Mo distances increase slightly. The strongly alternating ‘short’(mean 1.814 A) and ‘long’(1.990 A) Mo–O–Mo bonds in the unreduced compound 1 become more equal in 2. The structural changes upon reduction observed in 3 were analysed in detail. The most significant alterations are an increase of the Mo ⋯ Mo distances between corner-sharing MoO6 octahedra in the equatorial belt by 0.066 A, and a decrease of the Mo–O–Mo bond lengths connecting the two halves of the anion. The alternation of the Mo–O(bridge) bonds is nearly evened out after reduction. All structural changes observed in 2 and 3 are consistent with the description that the additional electrons occupy delocalised molecular orbitals extending over the Mo–Ob framework.
- Published
- 1995
50. 2-[2-(pyrrolidin-2-yl)propan-2-yl]-1H-pyrrole and its amide derivative 1-{2-[2-(1H-pyrrol-2-yl)propan-2-yl]pyrrolidin-1-yl}ethanone
- Author
-
Helen Stoeckli-Evans, Guillaume Journot, and Reinhard Neier
- Subjects
chemistry.chemical_compound ,chemistry ,Hydrogen bond ,Stereochemistry ,Amide ,Molecule ,General Medicine ,Crystal structure ,Dihedral angle ,General Biochemistry, Genetics and Molecular Biology ,Derivative (chemistry) ,Pyrrolidine ,Pyrrole - Abstract
In the title compounds, C11H18N2, (II), and C13H20N2O, (III), the pyrrolidine rings have twist conformations. Compound (II) crystallizes with two independent molecules (AandB) in the asymmetric unit. The mean planes of the pyrrole and pyrrolidine rings are inclined to one another by 89.99 (11) and 89.35 (10)° in moleculesAandB, respectively. In (III), the amide derivative of (II), the same dihedral angle is much smaller, at only 13.42 (10)°. In the crystal structure of (II), the individual molecules are linkedviaN—H...N hydrogen bonds to form inversion dimers, each with anR22(12) graph-set motif. In the crystal structure of (III), the molecules are linkedviaN—H...O hydrogen bonds to form inversion dimers with anR22(16) graph-set motif.
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.