title: Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors.
abstract: In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50of 8.3 μM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50= 0.0032 μM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laborotary of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, PR China. Electronic address: zhengyouguang@xzhmu.edu.cn.
authors.forename: You-Guang
authors.initials: YG
authors.lastname: Zheng
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Cai-Yun
authors.initials: CY
authors.lastname: Gao
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: An
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Yun-Sheng
authors.initials: YS
authors.lastname: Xue
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.affiliation: College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China. Electronic address: cbpeliuyinew@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors
keywords: 4-Anilinoquinazoline derivatives; Amino acid moiety; Apoptosis; HepG2