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Chemical Reviews Oct 2016Pd-catalyzed cross-coupling reactions that form C-N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds... (Review)
Review
Pd-catalyzed cross-coupling reactions that form C-N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C-N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.
Topics: Amidines; Aniline Compounds; Biological Products; Carbamates; Catalysis; Cyclization; Heterocyclic Compounds; Hydrazines; Hydrazones; Ligands; Palladium; Sulfonamides; Urea
PubMed: 27689804
DOI: 10.1021/acs.chemrev.6b00512 -
JAMA Oncology Nov 2018Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M...
IMPORTANCE
Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.
OBJECTIVE
To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.
DESIGN, SETTING, AND PARTICIPANTS
Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.
MAIN OUTCOMES AND MEASURES
Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.
RESULTS
Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).
CONCLUSIONS AND RELEVANCE
Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
Topics: Acrylamides; Aniline Compounds; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms
PubMed: 30073261
DOI: 10.1001/jamaoncol.2018.2969 -
Biological & Pharmaceutical Bulletin Nov 2021Aniline and its dimethyl derivatives reportedly become haematotoxic after metabolic N-hydroxylation of their amino groups. The plasma concentrations of aniline and its...
Aniline and its dimethyl derivatives reportedly become haematotoxic after metabolic N-hydroxylation of their amino groups. The plasma concentrations of aniline and its dimethyl derivatives after single oral doses of 25 mg/kg in rats were quantitatively measured and semi-quantitatively estimated using LC-tandem mass spectrometry. The quantitatively determined elimination rates of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline based on rat plasma versus time curves were generally rapid compared with those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The primary acetylated metabolites of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline, as semi-quantitatively estimated based on their peak areas in LC analyses, were more extensively formed than those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The areas under the curve of unmetabolized (remaining) aniline and its dimethyl derivatives estimated using simplified physiologically based pharmacokinetic models (that were set up using the experimental plasma concentrations) showed an apparently positive correlation with the reported lowest-observed-effect levels for haematotoxicity of these chemicals. In the case of 2,4-dimethylaniline, a methyl group at another C-positon would be one of the determinant factors for rapid metabolic elimination to form aminotoluic acid. These results suggest that rapid and extensive metabolic activation of aniline and its dimethyl derivatives occurred in rats and that the presence of a methyl group at the C-positon may generally suppress fast metabolic rates of dimethyl aniline derivatives that promote metabolic activation reactions at NH moieties.
Topics: Administration, Oral; Aniline Compounds; Animals; Area Under Curve; Hemolytic Agents; Hydroxylation; Male; Rats, Sprague-Dawley; Rats
PubMed: 34433705
DOI: 10.1248/bpb.b21-00589 -
The Journal of Toxicological Sciences 2022Although human urinary aniline and 2,6-dimethylaniline were unexpectedly detected in biomonitoring data, little is known about the daily intake doses of aniline and...
Forward and reverse dosimetry for aniline and 2,6-dimethylaniline in humans extrapolated from humanized-liver mouse data using simplified physiologically based pharmacokinetic models.
Although human urinary aniline and 2,6-dimethylaniline were unexpectedly detected in biomonitoring data, little is known about the daily intake doses of aniline and 2,6-dimethylaniline in the living environment or their relation to tolerable daily intake (TDI) values in humans. In the current study, to evaluate the daily oral intake of aniline and 2,6-dimethylaniline in humans, forward and reverse dosimetry was carried out using simplified in silico physiologically based pharmacokinetic (PBPK) modeling established using in vivo experimental pharmacokinetic data. These data were from humanized-liver mice after single oral doses of 100 mg/kg aniline (previously determined) and 116 mg/kg 2,6-dimethylanine (currently investigated). The in vivo elimination rates of 2,6-dimethylaniline from plasma in humanized-liver mice were generally slow compared with those of aniline. Faster in vitro metabolic elimination rates of aniline mediated by liver 9000 × g supernatant fractions from rats than those from humans may suggest the existence of higher first-pass effects in rats than in humanized-liver mice. In silico aniline and 2,6-dimethylaniline concentration curves in human urine after virtual oral administrations were estimated by human PBPK models created with data from humanized-liver mice. Reverse dosimetry analysis using human PBPK models estimated the daily intake of aniline, based on reported human urinary concentrations in biomonitoring data, to be roughly similar to the aniline TDI level. These results suggest that forward and reverse dosimetry using simplified human PBPK models founded on data from humanized-liver mice can be used to evaluate possible higher than expected exposures of aniline and 2,6-dimethylaniline in humans.
Topics: Humans; Mice; Rats; Animals; Aniline Compounds; Liver; Epichlorohydrin
PubMed: 36450497
DOI: 10.2131/jts.47.531 -
IARC Monographs on the Evaluation of... 1993
Review
Topics: Aniline Compounds; Animals; Carcinogens; Coloring Agents; Dogs; Environmental Pollutants; Female; Humans; Male; Mice; Mice, Inbred Strains; Rats; Rats, Inbred F344
PubMed: 8207864
DOI: No ID Found -
IARC Monographs on the Evaluation of... 1993
Review
Topics: Aniline Compounds; Animals; Carcinogens; Female; Hair Dyes; Humans; Male; Mice; Mice, Inbred Strains; Nitrophenols; Rats; Rats, Inbred F344
PubMed: 8207854
DOI: No ID Found -
Journal of the American Chemical Society Oct 2022In all known genetic polymers, molecular recognition via hydrogen bonding between complementary subunits underpins their ability to encode and transmit information, to...
In all known genetic polymers, molecular recognition via hydrogen bonding between complementary subunits underpins their ability to encode and transmit information, to form sequence-defined duplexes, and to fold into catalytically active forms. Reversible covalent interactions between complementary subunits provide a different way to encode information, and potentially function, in sequence-defined oligomers. Here, we examine six oligoarylacetylene trimers composed of aniline and benzaldehyde subunits. Four of these trimers self-pair to form two-rung duplex structures, and two form macrocyclic 1,3-folded structures. The equilibrium proportions of these structures can be driven to favor each of the observed structures almost entirely depending upon the concentration of trimers and an acid catalyst. Quenching the acidic trimer solutions with an organic base kinetically traps all species such that they can be isolated and characterized. Mixtures of complementary trimers form exclusively sequence-specific 3-rung duplexes. Our results suggest that reversible covalent bonds could in principle guide the formation of more complex folded conformations of longer oligomers.
Topics: Aniline Compounds; Benzaldehydes; DNA; Nucleic Acid Conformation; Polymers
PubMed: 36174969
DOI: 10.1021/jacs.2c06268 -
The American Journal of the Medical... May 1997Leflunomide is a new immunomodulatory drug that is effective in experimental models of autoimmune diseases and in allo or xenotransplantation. In a phase II clinical... (Review)
Review
Leflunomide is a new immunomodulatory drug that is effective in experimental models of autoimmune diseases and in allo or xenotransplantation. In a phase II clinical trial, leflunomide showed high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite A77 1726, which is a malononitrilamide. The in vitro and in vivo mechanisms of action of this class of compounds are not defined completely. Several malononitrilamide analogues and A77 1726 inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. Although no central molecular mechanism of action has been proposed to explain all the effects of the malononitrilamides, the inhibition of de novo pyrimidine biosynthesis and of cytokine- and growth factor receptor-associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered in daily dosages of 10 mg and 25 mg to patients with active rheumatoid arthritis. The improved efficacy of a 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Because of the long plasma half-life of A77 1726 (11 to 16 days), loading doses are necessary to achieve steady state concentrations. Phase III randomized, placebo-controlled trials that use daily dosages of 10 mg or 20 mg are under way in the United States and Europe to confirm and extend the results of the phase II study. Malononitrilamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation. If these analogues show efficacies and therapeutic indexes that are similar to leflunomide in these models and that have shorter half-lives than A77 1726 in phase I trials, the preclinical and phase I data will be used to select the analogues for phase II trials in organ transplant recipients.
Topics: Aniline Compounds; Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Clinical Trials as Topic; Crotonates; Graft Rejection; Humans; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Leflunomide; Molecular Structure; Nitriles; Organ Transplantation; Toluidines; Transplantation Immunology
PubMed: 9145039
DOI: 10.1097/00000441-199705000-00008 -
Molecules (Basel, Switzerland) Mar 2022In this study, a rapid and simple method based on accelerated solvent extraction (ASE) combined with gas chromatography-mass spectrometry (GC-MS) was established to...
In this study, a rapid and simple method based on accelerated solvent extraction (ASE) combined with gas chromatography-mass spectrometry (GC-MS) was established to determine the levels of aniline in soil. The matrix spike recovery rates of aniline were investigated by changing several experimental parameters such as vacuum freeze-drying, accelerated solvent extraction, sample transfer, nitrogen-blowing concentration and solvent exchange. Under optimized pretreatment conditions, the linearity of the method ranged from 0.5 to 20 μg mL for aniline, and the correlation coefficient was 0.999. Recoveries of aniline from quartz sand and soil ranged from 76% to 98%, while the precision was excellent with average inter-day and intraday values ranging (n = 6) from 3.1% to 7.5% and 2.0% to 6.9%, respectively. The limits of quantification of the method were 0.04 mg kg. Notably, the results show that the method we developed is simple, fast, low cost and can meet the requirements for the determination of aniline in soil samples, sewage sludge, river and pond sediments.
Topics: Aniline Compounds; Gas Chromatography-Mass Spectrometry; Soil; Solid Phase Extraction; Solvents
PubMed: 35408491
DOI: 10.3390/molecules27072092 -
Current Neuropharmacology 2019Aniline exposure leads to neuron and spleen toxicity specifically and makes diverse neurological effects and sarcoma that is defined by splenomegaly, hyperplasia, and... (Review)
Review
Aniline exposure leads to neuron and spleen toxicity specifically and makes diverse neurological effects and sarcoma that is defined by splenomegaly, hyperplasia, and fibrosis and tumors formation at the end. However, the molecular mechanism(s) of aniline-induced spleen toxicity is not understood well, previous studies have represented that aniline exposure results in iron overload and initiation of oxidative/nitrosative disorder stress and oxidative damage to proteins, lipids and DNA subsequently, in the spleen. Elevated expression of cyclins, cyclin-dependent kinases (CDKs) and phosphorylation of pRB protein along with increases in A, B and CDK1 as a cell cycle regulatory proteins cyclins, and reduce in CDK inhibitors (p21 and p27) could be critical in cell cycle regulation, which contributes to tumorigenic response after aniline exposure. Aniline-induced splenic toxicity is correlated to oxidative DNA damage and initiation of DNA glycosylases expression (OGG1, NEIL1/2, NTH1, APE1 and PNK) for removal of oxidative DNA lesions in rat. Oxidative stress causes transcriptional up-regulation of fibrogenic/inflammatory factors (cytokines, IL- 1, IL-6 and TNF-α) via induction of nuclear factor-kappa B, AP-1 and redox-sensitive transcription factors, in aniline treated-rats. The upstream signalling events as phosphorylation of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) could potentially be the causes of activation of NF-κB and AP-1. All of these events could initiate a fibrogenic and/or tumorigenic response in the spleen. The spleen toxicity of aniline is studied more and the different mechanisms are suggested. This review summarizes those events following aniline exposure that induce spleen toxicity and neurotoxicity.
Topics: Aniline Compounds; Animals; Carcinogens; Disease Models, Animal; Gene Expression Regulation; Neurotoxicity Syndromes; Rats; Splenic Diseases
PubMed: 30081786
DOI: 10.2174/1570159X16666180803164238