Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAFV600E inhibitors
| Autor: | Meng-Yue Zhao, Ya-Liang Zhang, Shu-Fu Wang, Jigar A. Makawana, Hai-Liang Zhu, Yin-Ling Zhu, Ping-Ting Zhu, Peng-Cheng Lv |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Quantitative structure–activity relationship Stereochemistry Clinical Biochemistry Quantitative Structure-Activity Relationship Pharmaceutical Science Antineoplastic Agents Pyrazole Biochemistry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Neoplasms Drug Discovery medicine Humans Vemurafenib Protein Kinase Inhibitors Molecular Biology Cell Proliferation biology Chemistry Organic Chemistry Active site Biological activity Combinatorial chemistry Molecular Docking Simulation Niacinamide biology.protein Pyrazoles Molecular Medicine V600E medicine.drug Discovery Studio |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:6201-6208 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2014.08.029 |
| Popis: | A series of novel 5-phenyl-1H-pyrazole derivatives (5 a-5 u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF(V600E) inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 μM for BRAF(V600E). Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF(V600E) active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives. |
| Databáze: | OpenAIRE |
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