Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors
文献类型：期刊论文
| 作者 | Lin, Jin1; Zhang, Zemin2; Lin, Xiongqiang2; Chen, Zhendong2; Luc, Tian3; Zha, Daijun1,2; Wang, Jian1,2; Xu, Xiuzhi1,2; Li, Zhulai1,2 |
| 刊名 | MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022 |
| 卷号 | 18期号:3页码:353-363 |
| ISSN号 | 1573-4064 |
| 关键词 | Pteridine derivatives EGFR inhibitor 2,2,2-trifluoroethoxy antitumor activity |
| DOI | 10.2174/1573406417666210604105923 |
| 通讯作者 | Li, Zhulai(lizhulai@126.com) |
| 英文摘要 | Background: Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for the anticancer therapy. Objective: This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. Methods: Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. Results: The compound 7m, with IC50 values of 27.40 mu M on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides, western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 mu M. The molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lied at the ATP binding site of EGFR kinase domain. Conclusion: The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the anti proliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor. |
| WOS关键词 | GEFITINIB ZD1839 ; POTENT ; MUTATIONS ; DISCOVERY ; DESIGN ; CANCER ; FLT3 ; DNA |
| 资助项目 | Natural Science Foundation of Fujian Province[2019J05073] ; Natural Science Foundation of Fujian Province[2018J01846] ; Joint Funds for the Innovation of Science and Technology of Fujian Province[2018Y9071] ; Program for the Middle-aged and Young Key Talents in Health System of Fujian Province[2019-ZQN-69] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| WOS记录号 | WOS:000745049100004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300565]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Zhulai |
| 作者单位 | 1.Fujian Med Univ, Fujian Key Lab Drug Target Discovery & Struct & F, Fuzhou, Peoples R China 2.Fujian Med Univ, Sch Pharm, Dept Med Chem, POB 350122, Fuzhou, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lin, Jin,Zhang, Zemin,Lin, Xiongqiang,et al. Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors[J]. MEDICINAL CHEMISTRY,2022,18(3):353-363. |
| APA | Lin, Jin.,Zhang, Zemin.,Lin, Xiongqiang.,Chen, Zhendong.,Luc, Tian.,...&Li, Zhulai.(2022).Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors.MEDICINAL CHEMISTRY,18(3),353-363. |
| MLA | Lin, Jin,et al."Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors".MEDICINAL CHEMISTRY 18.3(2022):353-363. |
入库方式： OAI收割
来源：上海药物研究所
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