1. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors.
- Author
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Yang YS, Yang B, Zou Y, Li G, and Zhu HL
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Dioxins chemical synthesis, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Molecular Docking Simulation, Molecular Structure, Protein Binding drug effects, Proto-Oncogene Proteins B-raf metabolism, Pyrazoles chemical synthesis, Quantitative Structure-Activity Relationship, Dioxins chemistry, Dioxins pharmacology, Drug Design, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Pyrazoles chemistry, Pyrazoles pharmacology
- Abstract
A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-Raf(V600E) and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04μM and GI50 value of 0.87μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf(V600E) from B-Raf(WT), C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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