Design,biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors |
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| Institution: | 1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China;2. Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China;1. Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt;2. Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;3. Pharmacology Department, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA;4. Pharmacotherapy Department, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan;1. Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T''s College of Pharmacy, Sangolli Rayanna Nagar, Dharwad, 580 002, India;2. Division of Polymers and Functional Materials, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India;3. Universite de Toulouse, UPS, Laboratoire de Synthese et Physico-chimie de Molecules d''Interet Biologique, LSPCMIB, 118 Roote de Narbonne, F-31062, Toulouse Cedex 9, France;4. Department of Polymer and Fiber System Engineering, Chonnam National University, 300 Yongbong-Dong, Bukgu, Gwangju, 500 757, South Korea;1. Department of Studies in Chemistry, Mangalore University, Mangalagangotri 574199, Karnataka, India;2. Department of Pharmacology, N.G.S.M. Institute of Pharmaceutical Sciences, Paneer Deralakatte 574160, Karnataka, India;3. Department of Biotechnology, Goa University, Goa 403206, India;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;2. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea;3. Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt;1. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan;2. Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800, Multan, Pakistan;3. Institute of Chemistry, University of the Punjab, Lahore, Pakistan |
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| 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. |
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| Keywords: | Break limit Triaryl pyrazoline Dioxin Antitumor activity B-Raf Selective 3D QSAR |
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