title: The combination of 4-anilinoquinazoline and cinnamic acid: a novel mode of binding to the epidermal growth factor receptor tyrosine kinase.
abstract: A novel type of cinnamic acid quinazoline amide derivatives (20-42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC(50)=0.94 μM for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. Docking simulation was performed to position compound 42 into the EGFR active site to determine the probable binding model. Analysis of the binding conformation of 42 in active site displayed compound 42 was stabilized by hydrogen bonding interactions with Lys822, which was different from other derivatives. In the further study, Compounds 43 and 44 had been synthesized and their biological activities were also evaluated, which were the same as that we expected. Compound 43 has demonstrated significant EGFR (IC(50)=0.12 μM) and tumor growth inhibitory activity as a potential anticancer agent.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.forename: Peng-Cheng
authors.initials: PC
authors.lastname: Lv
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Hong-Jia
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Hou
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Yong-Hao
authors.initials: YH
authors.lastname: Ye
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C029010:cinnamic acid; D066246:ErbB Receptors