2,4-二芳氨基嘧啶类化合物的合成及抗肿瘤活性研究
Study on the synthesis and antitumor activities of 2,4-diarylaminopyrimidines
于晓英 1珊娜瓦尔·热合买提江 2董秋男 1夏明钰 2张美慧 1董金华
作者信息
- 1. 沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳 110016
- 2. 沈阳药科大学生命科学与生物制药学院,辽宁沈阳 110016
- 折叠
摘要
目的 设计合成2,4-二芳氨基嘧啶类化合物并进行体外抗肿瘤活性筛选.方法 以邻苯二胺和取代嘧啶为起始原料,经6步反应合成2,4-二芳氨基嘧啶类化合物.采用MTT法对所合成化合物进行体外抗肿瘤活性测试.结果 合成了 15个未见文献报道的2,4-二芳氨基嘧啶类化合物,结构均经1H-NMR、ESI-MS谱确证.活性测试结果显示大部分化合物对A549细胞的抑制活性高于或相当于阳性对照奥希替尼.结论 在2,4-二芳氨基嘧啶结构的嘧啶环5位上引入卤素有利于提高化合物的抗肿瘤细胞增殖活性.
Abstract
Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase.The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation.Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways,tumor cells often have dysregulated EGFR signaling through receptor overexpression and mutation.EGFR inhibitors like osimertinib,bearing 2,4-diarylaminopyrimidine moiety,showed potent and selective EGFR inhibitory activities.For increasing the antitumor activity,fifteen 2,4-diarylaminopyrimidine derivatives were designed and synthesized using osimertinib as lead compound,from o-phenylenediamine via six-step reactions including nuleophilic substitution,reduction and acylation.The structures of the target compounds were confirmed by 1H-NMR and ESI-MS.The in vitro anti-proliferative effects of the target compounds on A549 cells were determined by MTT assay.Preliminary pharmacological results showed that the introduction of halogen atom at the C5 position of pyrimidinyl moiety can improve the antiproliferative effect.
关键词
2,4-二芳氨基嘧啶/抗肿瘤活性/合成Key words
2,4-diarylaminopyrimidine/antitumor activity/synthesis引用本文复制引用
出版年
2024
NETL
NSTL
万方数据