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

Yu Shun Yang, Bing Yang, Yan Zou, Guigen Li, Hai Liang Zhu

Research output: Contribution to journalArticle

16 Scopus citations

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 languageEnglish
Pages (from-to)3052-3061
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number13
DOIs
StatePublished - Jul 1 2016

Keywords

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

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