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-RafV600E and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04 μM and GI50 value of 0.87 μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-RafV600E from B-RafWT, 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.
Original language | English |
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Pages (from-to) | 3052-3061 |
Number of pages | 10 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 24 |
Issue number | 13 |
DOIs | |
State | Published - Jul 1 2016 |
Keywords
- 3D QSAR
- Antitumor activity
- B-Raf
- Break limit
- Dioxin
- Selective
- Triaryl pyrazoline