title: Design and Synthesis of Vandetanib Derivatives Containing Nitroimidazole Groups as Tyrosine Kinase Inhibitors in Normoxia and Hypoxia.
abstract: Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a-p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50value (1.64 μmol/L), the inhibition ratios of16fover A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 μM in hypoxia, respectively. All of these results indicated that16fwas a potential cancer therapeutic agent in hypoxia and was worthy of further development.
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China. wakie0208@163.com.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Wei
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China. ldguan@163.com.
authors.forename: Deguan
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China. 15122363480@163.com.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China. shanghaihua2005@163.com.
authors.forename: Haihua
authors.initials: H
authors.lastname: Shang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China. fansaijun@163.com.
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China. liyiliang@irm-cams.ac.cn.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Chongqing Technical Center for Drug Evaluation & Certification, Chongqing 400014, China. songdan1995@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Song
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D009593:Nitroimidazoles / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D009593:Nitroimidazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D010100:Oxygen; C452423:vandetanib
keywords: hypoxia; nitroimidazole; tyrosine kinase inhibitor; vandetanib