title: Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity.
abstract: 1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 μg/ml and 10.21 μg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 μM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Luo
authors.forename: Liang-Qiang
authors.initials: LQ
authors.lastname: He
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Ai-Qin
authors.initials: AQ
authors.lastname: Jiang
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Yang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D014230:Triazoles; C583463:1,3,4-oxadiazole; C012771:benzotriazole; D051416:Focal Adhesion Protein-Tyrosine Kinases