title: Design, modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents.
abstract: Two series of novel naphthalin-containing pyrazoline derivatives C1-C14 and D1-D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC(50)=0.05 μM and GI(50)=0.11 μM), being comparable with the positive control Erlotinib (IC(50)=0.03 μM and GI(50)=0.03 μM) and more potent than our previous compounds C0-A (IC(50)=5.31 μM and GI(50)=33.47 μM) and C0-B (IC(50)=0.09 μM and GI(50)=0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC(50)=0.88 μM and GI(50)=0.35 μM), being a little less potent than Erlotinib (IC(50)=0.16 μM and GI(50)=0.08 μM) but far more potent than C0-A (IC(50)=6.58 μM and GI(50)=27.62 μM) and C0-B (IC(50)=2.77 μM and GI(50)=3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets.
authors: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors: Wen
authors: W
authors: Yang
authors: Yang
authors: Y
authors: Hu
authors: Yu-Shun
authors: YS
authors: Yang
authors: Fei
authors: F
authors: Zhang
authors: Yan-Bin
authors: YB
authors: Zhang
authors: Xiao-Liang
authors: XL
authors: Wang
authors: Jian-Feng
authors: JF
authors: Tang
authors: Wei-Qing
authors: WQ
authors: Zhong
authors: Hai-Liang
authors: HL
authors: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry / Q000633:toxicity; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013890:Thiourea / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D009281:Naphthalenes; D011720:Pyrazoles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013890:Thiourea; C031721:naphthalene