Design,synthesis,antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives  

作　　者：Hai-hong LI Xiu-hua ZHANG Jin-zhi TAN Li-li CHEN Hong LIU Xiao-min LUO Xu SHEN Li-ping LIN Kai-xian CHEN Jian DING3, Hua-liang JIANG 

机构地区：[1]Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai 201203, China [2]Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China [3]School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

出　　处：《Acta Pharmacologica Sinica》2007年第1期140-151,152,共13页中国药理学报（英文版）

基　　金：Project supported by the State Key Program of Basic Research of China(No 2002CB512802);the 863 Hi-Tech Program(No 2002AA233061 and 2003AA235011);the National Natural Science Foundation of China(No 20372069,29725203 and 20472094).

摘　　要：Aim： To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework. Methods： Based on enzyme binding features of （Z）-SU5402, introducing a β-pyrrole group at the 3-position of the indolin- 2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay. Results： Twenty new compounds （la-t） with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance （NMR） spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine ldnases, the cell-based antitumor activity was promising. Compounds lg and lh showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC50 of 0.065-9.4 μmol/L. Conclusion： This study provides a new template for further development of potent antitumor drugs.Aim： To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework. Methods： Based on enzyme binding features of （Z）-SU5402, introducing a β-pyrrole group at the 3-position of the indolin- 2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay. Results： Twenty new compounds （la-t） with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance （NMR） spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine ldnases, the cell-based antitumor activity was promising. Compounds lg and lh showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC50 of 0.065-9.4 μmol/L. Conclusion： This study provides a new template for further development of potent antitumor drugs.

关 键 词：protein-tyrosine kinase INDOLIN-2-ONE antitumor drug screening assays drugdesign molecular models 

分 类 号：R979.14[医药卫生—药品]