title: Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors.
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.
authors.affiliation: 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.
authors.forename: Yu-Shun
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. Electronic address: guigenli@nju.edu.cn.
authors.forename: Guigen
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004147:Dioxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004147:Dioxins; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf
keywords: 3D QSAR; Antitumor activity; B-Raf; Break limit; Dioxin; Selective; Triaryl pyrazoline