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Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Anticancéreux, Antineoplastic agents, Généralités, General aspects, Enzyme, Enzima, Transferases, Anticancéreux, Antineoplastic agent, Anticanceroso, In vitro, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Protein-tyrosine kinase, Relation structure activité, Structure activity relation, Relación estructura actividad, Récepteur facteur croissance épiderme, Epidermal growth factor receptor, Receptor factor crecimiento epidermi, Synthèse chimique, Chemical synthesis, Síntesis química, Transduction signal, Signal transduction, Transducción señal, Lignée DiFi, Pyrimido[4,5-b][1,4]benzodiazépine dérivé, Pyrimido[4,5-b][1,4]benzooxazépine dérivé, Pyrimido[4,5-b][1,4]benzothiazépine dérivé, Pyrimidobenzodiazépine, Pyrimidobenzooxazépine, Pyrimidobenzothiazépine, Diazepine, Kinase inhibitor, Oxazepine, and Thiazepine

Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC50 values in the single-digit micromolar to submicromolar range).

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Divers, Miscellaneous, Enzyme, Enzima, Halogène Composé organique, Halogen Organic compounds, Halógeno Compuesto orgánico, Transferases, Composé aromatique, Aromatic compound, Compuesto aromático, Composé tricyclique, Tricyclic compound, Compuesto tricíclico, Hétérocycle oxygène azote, Oxygen nitrogen heterocycle, Heterociclo oxígeno nitrógeno, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Inhibition, Inhibición, Lactame, Lactam, Lactamo, Protein-tyrosine kinase, Relation structure activité, Structure activity relation, Relación estructura actividad, Récepteur facteur croissance épiderme, Epidermal growth factor receptor, Receptor factor crecimiento epidermi, Synthèse chimique, Chemical synthesis, Síntesis química, Sélectivité, Selectivity, Selectividad, Transduction signal, Signal transduction, Transducción señal, Pyrimido[4,5-b][1,4]benzooxazépine dérivé, Pyrimidobenzooxazépine, Benzoxazepine, Kinase inhibitor, and Kinase selectivity

A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 μM in cellular phosphorylation assays (IC50 0.47-0.69 μM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Anticancéreux, Antineoplastic agents, Généralités, General aspects, Mammalia, Rodentia, Vertebrata, Animal, Anticancéreux, Antineoplastic agent, Anticanceroso, Antimitotique, Antimitotic, Antimitótico, Antitubuline, Antitubulin, Antitubulina, Carcinome épidermoïde, Squamous cell carcinoma, Carcinoma epidermoide, Cellule tumorale, Tumor cell, Célula tumoral, Composé bicyclique, Bicyclic compound, Compuesto bicíclico, Cytotoxicité, Cytotoxicity, Citotoxicidad, Homme, Human, Hombre, Hétérocycle oxygène azote, Oxygen nitrogen heterocycle, Heterociclo oxígeno nitrógeno, Hétérocycle oxygène, Oxygen heterocycle, Heterociclo oxígeno, In vitro, In vivo, Lignée cellulaire, Cell line, Línea celular, Oxadiazole dérivé, Oxadiazole derivatives, Oxadiazol derivado, Pharmacocinétique, Pharmacokinetics, Farmacocinética, Pyridine dérivé, Pyridine derivatives, Piridina derivado, Relation structure activité, Structure activity relation, Relación estructura actividad, Souris, Mouse, Ratón, Synthèse chimique, Chemical synthesis, Síntesis química, Voie intrapéritonéale, Intraperitoneal administration, Vía intraperitoneal, Voie orale, Oral administration, Vía oral, 1,3,4-Oxadiazole(2-[(1,3-benzodioxol-5-yl)amino]-5-[(2-picolylamino)-3-pyridyl]), 1,3-Benzodioxole dérivé, Benzo[a]heptalène dérivé, Benzoheptalène, Lignée A431, 1,3,4-Oxadiazole, Antimitotic agent, Multiple-drug resistance, and Tubulin polymerization inhibitor

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 μM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC50 = 7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.