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  3. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors

Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors

  • Bioorg Med Chem. 2016 Jul 1;24(13):3052-3061. doi: 10.1016/j.bmc.2016.05.012.
Yu-Shun Yang 1,  Bing Yang 2,  Yan Zou 1,  Guigen Li 3,  Hai-Liang Zhu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China; Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
  • 2 Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
  • 3 Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. Electronic address: guigenli@nju.edu.cn.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China. Electronic address: zhuhl@nju.edu.cn.
PMID: 27238841 DOI: 10.1016/j.bmc.2016.05.012
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.

Keywords

3D QSAR; Antitumor activity; B-Raf; Break limit; Dioxin; Selective; Triaryl pyrazoline.

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