Oxalyl Chloride as a Practical Carbon Monoxide Source for Carbonylation Reactions

A method for generation of high-quality carbon monoxide by decomposition of oxalyl chloride in an aqueous hydroxide solution is described. The usefulness of the method is demonstrated in the synthesis of heterocycles and for hydroxy-, alkoxy-, amino-, and reductive carbonylation reactions, in several cases under milder conditions than previously reported

Continuous Flow Nucleophilic Aromatic Substitution with Dimethylamine Generated in Situ by Decomposition of DMF

A safe, practical, and scalable continuous flow protocol for the in situ generation of dimethylamine from DMF followed by nucleophilic aromatic substitution of a broad range of aromatic and heteroaromatic halides is reported

Discovery of a Potent and Selective GPR120 Agonist

GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist

Dihydropyridine Fluorophores Allow for Specific Detection of Human Antibodies in Serum

Antigen recognition by antibodies plays an important role in human biology and in the development of diseases. This interaction provides a basis for multiple diagnostic assays and is a guide for treatments. We have developed dihydropyridine-based fluorophores that form stable complexes with double-stranded DNA and upon recognition of the antibodies to DNA (anti-DNA) provide an optical response. The fluorophores described herein have advantageous optical properties compared to those of the currently available dyes making them valuable for research and clinical diagnostics. By studying a series of novel fluorophores, crucial parameters for the design were established, providing the required sensitivity and specificity in the detection of antibodies. Using these DNA–fluorophore complexes in a direct immunofluorescence assay, antibodies to DNA are specifically detected in 80 patients diagnosed with an autoimmune disease, systemic lupus erythematosus. Positivity indicated by emission change of α-(4′-<i>O</i>-methoxyphenyl)-2-furyl dihydropyridine strongly correlates with other disease biomarkers and autoimmune arthritis

Additional file 1: Figure S1. of Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation

Testing the specificity of the antibodies against GPR120 and GPR40. Figure S2 specific activation of GPR120 and GPR40. (PDF 10063 kb

PGH₁ activates human Th2 cells via CRTH2.

<p>Induction of Ca²⁺ mobilization (A–C) and cell migration (D–F) in human Th2 cells in response to the indicated concentrations of PGD₂, PGH₁, and PGH₂, respectively. The level of cell migration in response to medium without agonist was set to 1 fold. Both Ca²⁺ mobilization and cell migration are inhibited in the presence of 1 µM of the CRTH2 specific antagonist TM30089. Pooled data is expressed as the mean ± SEM from 3 experiments conducted in duplicate, each experiment involving Th2 cells from a separate donor. Statistical analysis was performed for vehicle vs. TM30089 treated cells and is indicated as (*) for p<0.05, as (**) for p<0.01 and as (***) for p<0.001.</p

PGH₁ activates human eosinophils via CRTH2.

<p>Human eosinophils were treated with the indicated concentrations of PGD₂, PGH₁, and PGH₂, respectively, and chemotactic activation was measured in eosinophil shape change assays. Eosinophil shape change is inhibited in the presence of 1 µM of the CRTH2-specific antagonist TM30089. Note: rank order of PG potency matches well with the results obtained in CRTH2-HEK transfectants using DMR assays (compare with <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033329#pone-0033329-g001" target="_blank"><b>Figure 1F</b></a>). Results are expressed as the mean ± SEM of 3 experiments conducted in triplicate with a separate donor used in each experiment. Statistical analysis was performed for vehicle vs. TM30089 treated cells and is indicated as (**) for p<0.01 and as (***) for p<0.001.</p

Prostaglandin H₁ (PGH₁) stimulates Ca²⁺ mobilization from intracellular stores in CRTH2 transfectants and primary human eosinophils.

<p><b>A</b>–<b>D</b>: HEK293 cells stably expressing CRTH2 (CRTH2-HEK) were transiently transfected with a chimeric Gαqi5 protein to channel the Gi-sensitive CRTH2 receptor to mobilization of intracellular Ca²⁺. Cells were loaded with a Ca²⁺ fluorophore and CRTH2-specific Ca²⁺ traces were recorded over time upon challenge with the indicated agonists (<b>A</b>: PGD₂, <b>B</b>: PGH₁, <b>C</b>: PGH₂). <b>A</b>–<b>C</b>: representative data (mean + SEM of triplicate determinations. <b>D</b>: Maximum responses of all experiments were normalized to Ca²⁺ flux induced by 1 µM PGD₂ (mean + SEM, n = 3). <b>E</b>: PGH₁ induces Ca²⁺ mobilization in human eosinophils via CRTH2. Intracellular free Ca²⁺ levels were quantified by flow cytometry as described in the methods section. The level of Ca²⁺ mobilization in response to vehicle without agonist was set to 100%. Ca²⁺ mobilization upon addition of PGH₁, PGH₂, and PGD₂ is inhibited in the presence of 1 µM of the CRTH2 specific antagonist TM30089. Data are presented as the mean + SEM from 5 experiments conducted in triplicate, each experiment involving eosinophils from a separate donor.</p

Structure–Activity Relationships and Identification of Optmized CC-Chemokine Receptor CCR1, 5, and 8 Metal-Ion Chelators

Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2′-bipyridine, 1,10-phenanthroline, and 2,2′;6′,2″-terpyridine. Here, we have performed an in-depth structure–activity relationship study and tested eight new optimized analogs. Using density functional theory calculations we demonstrate that the chelator zinc affinities depend on how electron-donating and -withdrawing substituents modulate the partial charges of chelating nitrogens. The zinc affinity was found to constitute the major factor for receptor potency, although the activity of some chelators deviate suggesting favorable or unfavorable interactions. Hydrophobic and halogen substituents are generally better accommodated in the receptors than polar groups. The new analog brominated terpyridine (<b>29</b>) resulted in the highest chelator potencies observed so far CCR1 (EC₅₀: 0.49 μM) and CCR8 (EC₅₀: 0.28 μM). Furthermore, we identified the first selective CCR5 agonist chelator, meta dithiomethylated bipyridine (<b>23</b>). The structure–activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation

PGH₁ induces eosinophil adhesion to human pulmonary microvascular endothelial cells under flow conditions.

<p>Eosinophils were pre-incubated with vehicle (<b>A</b>–<b>C</b>) or 10 µM CRTH2-specific antagonist TM30089 (<b>D</b>–<b>F</b>) for 10 min at room temperature followed by treatment with vehicle (<b>A</b>, <b>D</b>), 1 µM PGH₁ (<b>B</b>, <b>E</b>) or 30 nM PGD₂ (<b>C</b>, <b>F</b>) for 10 min at 37°C. Eosinophils were then superfused over human pulmonary microvascular endothelial cells grown on VenaEC biochips (Cellix, Dublin) for 5 min at 37°C. Representative images were taken 5 min after start of the superfusion (<b>A</b>–<b>F</b>). <b>G</b>: averaged data from <b>A</b>–<b>F</b>, quantified by computerized image analysis. Data are shown as mean + SEM of 4 experiments. *P<0.05 PGD₂ versus TM30089+PGD₂ and PGH₁ versus TM30089+PGH₁.</p