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Journal of Medicinal Chemistry Aug 2019The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine...
The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo[1,2-]pyrazine, imidazo[1,5-]quinoxaline, and pyrazolo[1,5-]quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo[1,5-]quinoxaline series ( and ) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.
Topics: Cell Line; Dose-Response Relationship, Drug; Humans; Imidazoles; Protein Structure, Secondary; Pyrazines; Quinoxalines; Toll-Like Receptor 7
PubMed: 31283223
DOI: 10.1021/acs.jmedchem.9b00411 -
Expert Opinion on Investigational Drugs Aug 2020Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from... (Comparative Study)
Comparative Study Review
Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from satisfactory. Prexasertib (LY2606368) is a novel checkpoint kinase inhibitor (CHK) under investigation for the treatment of HGSOC. Data from a recent phase II trial showed promising efficacy and safety results for treating wild-type BRCA HGSOC. Areas covered This article reviews the available data on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of prexasertib in the treatment of HGSOC. Expert opinion Until now, prexasertib demonstrated clinical activity in phase I and II clinical trial for treating wild-type BRCA HGSOC, whereas its promising efficacy as monotherapy and combined with olaparib in BRCA-mutated HGSOC has been preliminary evidenced only in phase I studies. Compared to other drugs of the same class, prexasertib showed a better tolerability profile, causing moderate hematological toxicity. Further studies are needed to confirm efficacy and safety profiles of prexasertib in combined regimens. New early clinical trials may investigate prexasertib administered with programmed cell death ligand 1 (PD-L1) and PI3 K inhibitors due to the preclinical evidence of a synergic action.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cystadenocarcinoma, Serous; Drug Synergism; Female; Humans; Neoplasm Grading; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyrazines; Pyrazoles
PubMed: 32539469
DOI: 10.1080/13543784.2020.1783238 -
Chembiochem : a European Journal of... Feb 2020Pyrazines are widespread chemical compounds that include pheromones and odors. Herein, a novel mechanism used by Pseudomonas fluorescens SBW25 to biosynthesize...
Pyrazines are widespread chemical compounds that include pheromones and odors. Herein, a novel mechanism used by Pseudomonas fluorescens SBW25 to biosynthesize monocyclic pyrazines is reported. Heterologous expression of the papABC genes that synthesize the natural α-amino acid 4-aminophenylalanine (4APhe), together with three adjacent papDEF genes of unknown function, in Escherichia coli resulted in the production of 2,5-dimethyl-3,6-bis(4-aminobenzyl)pyrazine (DMBAP), which comprised two symmetrical aminobenzyl moieties derived from 4APhe. It is found that PapD is a novel amino acid C-acetyltransferase, which decarboxylates and transfers acetyl residues to 4APhe, to generate an α-aminoketone, which spontaneously dehydrates and condenses to give dihydro DMBAP. PapF is a novel oxidase in the amine oxidase superfamily that oxidizes dihydro DMBAP to yield the pyrazine ring of DMBAP. These two enzymes constitute a unique mechanism for synthesizing monocyclic pyrazines and might serve as a novel strategy for the enzymatic synthesis of pyrazine derivatives from natural α-amino acids.
Topics: Acetyltransferases; Amino Acids; Molecular Structure; Oxidoreductases; Pseudomonas fluorescens; Pyrazines
PubMed: 31322801
DOI: 10.1002/cbic.201900448 -
Food Research International (Ottawa,... Sep 2022This study aimed to evaluate the volatile compounds of chocolates made of Brazilian cocoas and statistically track them according to the products' sensorial profile in...
This study aimed to evaluate the volatile compounds of chocolates made of Brazilian cocoas and statistically track them according to the products' sensorial profile in order to relate them to consumers' acceptance by preference map methodology. The intensity of the chocolate, acidity, woody, smoked, green, floral, burned, musty, and cocoa notes from chocolates produced with cocoa from different Brazilian states were analyzed by a trained panel and by 128 consumers. Samples from Côte d'Ivoire, which is known for its high-quality chocolate, were evaluated for comparison. Solid-phase microextraction headspace sampling/gas chromatography-mass spectrometry was employed to evaluate the samples' volatile compounds. One hundred volatile compounds were identified within the samples. The results from the preference maps showed that the maximum preference was found for chocolate made of cocoa from Rondônia, Bahia, and Espírito Santo and Côte d'Ivoire and organic samples from Pará. The ideal sample point was characterized by intense chocolate, floral, and woody notes and mild green and burned notes. The presence of furfural, 3-methyl butanal, phenethyl acetate, 2-phenyl-5-methyl-2-hexenal, methyl pyrazine, phenethyl acetate, 2-phenyl-5-methyl-2-hexenal, and tetramethyl pyrazine were shown to be important for consumer acceptance in the ideal product, whereas the presence of (Z)-2-heptenal and 2-pentyl furan may increase consumer rejection. 2,3-Methyl pyrazine, methyl pyrazine, and 2,3-butanediol, which are important volatile compounds previously reported in the literature, were statistically tracked to both positive and negative sample attributes and must be better explored concerning consumers' acceptance of chocolates.
Topics: Brazil; Cacao; Chocolate; Pyrazines; Taste; Volatile Organic Compounds
PubMed: 35940809
DOI: 10.1016/j.foodres.2022.111618 -
Molecular Diversity May 2021Isocyanides as key intermediates and magic reactants have been widely applied in organic reactions for direct access to a broad spectrum of remarkable organic compounds.... (Review)
Review
Isocyanides as key intermediates and magic reactants have been widely applied in organic reactions for direct access to a broad spectrum of remarkable organic compounds. Although the history of these magical compounds dates back more than 100 years, it still has been drawing widespread attention of chemists who confirmed their versatility and effectiveness. Because of their wide spectrum of pharmacological, industrial and synthetic applications, many reactions with the utilization of isocyanides are reported in the literature. In this context, Iranian scientist played a significant role in the growth of isocyanides chemistry. The present review article covers literature from the period starting from 2010 onward and encompasses new synthetic routes and organic transformation involving isocyanides by Iranian researchers. During this period, a diverse range of isocyanide-based multi-component reactions (I-MCRs) has been reported such as a new modification of Ugi, post-Ugi, Passerini and Groebke-Blackburn-Bienayme condensation reactions, isocyanide-based [1 + 4] cycloaddition reactions, isocyanide-acetylene-based MCRs, isocyanide and Meldrum's acid-based MCRs, several unexpected reactions besides green mediums and novel catalytic systems for the synthesis of diverse kinds of pharmaceutically and industrially remarkable heterocyclic and linear organic compounds. This review also emphasizes the neoteric applications of I-MCR for the synthesis of valuable peptide and pseudopeptide scaffolds, enzyme immobilization and functionalization of materials with tailorable properties that can play important roles in the plethora of applications.
Topics: Chemistry Techniques, Synthetic; Cyanides; Heterocyclic Compounds, 2-Ring; Iran; Metals; Pyrazines
PubMed: 32072381
DOI: 10.1007/s11030-020-10049-7 -
Bioorganic & Medicinal Chemistry Letters Oct 2022We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction...
We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.
Topics: Cyclization; Mitochondria; Oxadiazoles; Pyrazines
PubMed: 35907607
DOI: 10.1016/j.bmcl.2022.128912 -
Water Research Sep 2020The presence of earthy-musty odors in drinking water is a major concern for water suppliers and consumers worldwide. While geosmin and 2-methylisoborneol are the most...
The presence of earthy-musty odors in drinking water is a major concern for water suppliers and consumers worldwide. While geosmin and 2-methylisoborneol are the most studied earthy-musty odor-causing compounds, pyrazine and its alkyl and methoxy compounds possess similar odors and are widely distributed in nature, foods, and beverages. In this study, odor characteristics of pyrazines and their presence in natural and treated waters were determined. Pyrazine, 2,6-dimethyl-pyrazine (DMP), 2,3,5-trimethyl-pyrazine (TrMP), 2-ethyl-5(6)-methyl-pyrazine (EMP), 2,3,5,6-tetramethyl-pyrazine (TeMP), 2-isobutyl-3-methoxy-pyrazine (IBMP) and 2-isopropyl-3-methoxy-pyrazine (IPMP) were measured in source and finished drinking water across China. 2-Methoxy-3,5-dimethyl-pyrazine (MDMP), IBMP, and IPMP were investigated in rivers in Virginia, USA. The results showed that "musty" and "sweet" were the most common descriptors for pyrazine, DMP, MDMP, TrMP, and TeMP. While IBMP and IPMP were never detected in 140 source or drinking water samples from across China, pyrazine, DMP, MDMP, TrMP, and TeMP occurred throughout with concentrations of n.d.-62.2 ng/L-aq in source water and n.d.-39.6 ng/L-aq in finished water. IBMP, IPMP, and MDMP were present in two Virginia rivers; MDMP occurred in 18% of the samples with concentrations of n.d.-4.4 ng/L, many of which were above the aqueous odor threshold of 0.043 ng/L MDMP. The removal efficiencies through conventional water treatment were poor, ranging from negative removals to ∼10%. Advanced oxidation water treatment could only remove EMP and TrMP. The widespread presence of earthy-musty-sweet pyrazines in source and drinking waters on two continents, their poor removal during water treatment, and ng/L odor threshold concentrations confirm their potential to be T&O issues for consumers.
Topics: China; Consumer Behavior; Drinking Water; Odorants; Pyrazines; Virginia; Water Pollutants, Chemical
PubMed: 32554269
DOI: 10.1016/j.watres.2020.115971 -
Journal of Clinical Pharmacology Oct 2020Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare... (Clinical Trial)
Clinical Trial Comparative Study
Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.
Topics: Adult; Aged; Area Under Curve; Diabetic Neuropathies; Enzyme Inhibitors; Female; Healthy Volunteers; Humans; Liver Diseases; Male; Middle Aged; Protein Binding; Pyrazines; Spiro Compounds
PubMed: 32437025
DOI: 10.1002/jcph.1636 -
Blood Cancer Journal Nov 2023
Topics: Humans; Bortezomib; Multiple Myeloma; Standard of Care; Pyrazines; Physicians
PubMed: 37926718
DOI: 10.1038/s41408-023-00937-0 -
Talanta Jul 2023Gas chromatography coupled with ion mobility spectrometry (IMS) is an analytical tool which is rapidly becoming widespread in the analysis of food volatiles. Despite...
Gas chromatography coupled with ion mobility spectrometry (IMS) is an analytical tool which is rapidly becoming widespread in the analysis of food volatiles. Despite this increasing popularity, an assessment of the IMS response for several flavor compound classes is not yet available. This study focuses on alkyl pyrazines and their determination in roasted hazelnut pastes. These Maillard reaction products are crucial to determine the aromatic profile of roasted foods and are suitable markers for industrial roasting monitoring. The instrumental response of 8 alkyl pyrazines was studied using a model matrix and a matrix matching approach. The results showed a relevant effect of the pyrazine ring substitution pattern on the concentration-response curve trends, highlighting that an external standardization of the IMS response is required to make possible relative abundance comparisons between analytes. A response standardization was therefore developed and applied to determine alkyl pyrazines in samples with different roasting intensity and geographical and botanical origin.
Topics: Gas Chromatography-Mass Spectrometry; Corylus; Pyrazines; Ion Mobility Spectrometry; Volatile Organic Compounds
PubMed: 37088040
DOI: 10.1016/j.talanta.2023.124568