Modification, biological evaluation and 3D QSAR studies of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives as inhibitors of B-Raf kinase.
A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1-C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM) and WM266.4 human melanoma cell line (GI50 = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China; Institute of Chemical and Biomedical Science, Nanjing University, Nanjing, P. R. China.
Yu-Shun
YS
Yang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China.
Fei
F
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China.
Dan-Jie
DJ
Tang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China.
Yong-Hua
YH
Yang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China.
Hai-Liang
HL
Zhu
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D062105:Molecular Docking Simulation; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf