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

doi:10.1016/j.bmc.2016.05.012

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. Epub 2016 May 12.

Authors

Yu-Shun Yang¹, Bing Yang², Yan Zou¹, Guigen Li³, Hai-Liang Zhu⁴

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.

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Dioxins / chemical synthesis
Dioxins / chemistry*
Dioxins / pharmacology*
Drug Design*
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 / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Quantitative Structure-Activity Relationship

Substances

Dioxins
Enzyme Inhibitors
Pyrazoles
Proto-Oncogene Proteins B-raf