title: Discovery of 4,6-substituted-(diaphenylamino)quinazolines as potent c-Src inhibitors.
abstract: A series of 4,6-substituted-(diaphenylamino)quinazolines as c-Src inhibitors have been prepared and their biological activity has also been evaluated. All the compounds displayed potential antiproliferation activities, with IC50 values ranging from 3.42 μM to 118.81 μM in five human tumor cell lines. Particularly, compound 15 exhibited higher cytotoxicity against the tested five tumor cell lines compared to the other small molecules. Generally, most of these compounds showed selectivity between the A549 cells and the other four cells, according to their corresponding IC50 values. The results obtained from the in vitro enzyme assay indicated compound 15 has remarkable inhibitory activity against c-Src kinase with an IC50 value of 27.3 nM, which is comparable to the control compounds. Furthermore, molecular docking and QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. zhuhl@nju.edu.cn.
authors.forename: Jing-Ran
authors.initials: JR
authors.lastname: Li
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: Qian-Ru
authors.initials: QR
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Yong
authors.initials: Y
authors.lastname: Qian
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human