thiopental-sodium and pyrimidine

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; ErbB Receptors; Humans; Male; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Neoplasms, Experimental; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 - 750) or Z'LYTE assay method (EGFR-WT, EGFR d746 - 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho-hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10µM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9-12 exhibited complete inhibition at 10µM and nearly complete inhibition at 1µM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7, 9-12, 30 and 31 were found to be the most potent compounds across all five cell lines.

Topics: Acrylamides; Animals; Cell Line, Tumor; Cell Survival; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Mice; Mutagenesis, Site-Directed; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship

To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a-h were synthesized and biologically evaluated. Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Resistance, Neoplasm; Enzyme Activation; ErbB Receptors; Free Radical Scavengers; Gefitinib; Humans; Nitric Oxide; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Signal Transduction