Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor treatment
| Autor: | Feng Jin, Bizhu Chu, Chen Yan, Yuyang Jiang, Dan Gao, Chunyan Tan, Feng Liu, Cunlong Zhang, Yu Zong Chen |
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| Rok vydání: | 2013 |
| Předmět: |
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Molecular Dual inhibition Stereochemistry Clinical Biochemistry Phenylurea Derivatives Pharmaceutical Science Antineoplastic Agents Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Benzopyrans Mitogen-Activated Protein Kinase 8 Protein Kinase Inhibitors Molecular Biology Cell Proliferation Antitumor activity Dose-Response Relationship Drug Molecular Structure Chemistry Kinase Phenylurea Compounds Organic Chemistry Hep G2 Cells Proto-Oncogene Proteins c-raf Hepg2 cells Toxicity Urea Molecular Medicine Drug Screening Assays Antitumor Binding domain |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:824-831 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.04.006 |
| Popis: | Based on the roles of Raf1 and JNK1 in hepatocarcinoma development, scaffold-based drug design was employed to produce a series of compounds, which subsequently were synthesized and explored as potential dual inhibitors Raf1 and JNK1 kinases for anti-tumor treatment. The compound 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chloro-phenyl)urea (3d) showed 66%, 67% and 13% inhibition rate at 50 μM against Raf1, JNK1 and p38-alpha, respectively, but no effect on ERK1 and ERK2, and inhibited the expression of pERK1/2 markedly and HepG2 cells proliferation with IC(50) at 8.3 μM. Furthermore, 3d showed lower toxicity against normal liver cell-lines QSG7701 and HL7702. Molecular docking study further showed that 3d can fit into binding domain of JNK1 and Raf1. Our data suggested the activities of 3d were associated with dual inhibition of JNK1 and Raf1 kinases. |
| Databáze: | OpenAIRE |
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