新型嘧啶类化合物的合成及抗肿瘤活性

摘要基于已报道的ALK激酶抑制剂，对NVP-TAE684进行结构改造，将起始化合物1经过胺化引入吡嗪氮杂环（2），再脱Boc反应获得胺中间体（3），最后3与亲电试剂6通过钯催化C-N偶联反应合成了2个吡嗪氮杂环修饰的嘧啶衍生物（7a，7b）。中间体2，3和目标化合物7未见文献报导，6个新化合物结构均经¹H NMR、¹³C NMR和HRMS-ESI确定。采用MTT法考察了目标化合物对肿瘤细胞NCI-H460和NCI-H520的体外抑制活性。结果表明，化合物7a和7b对肿瘤细胞均具有明显的抑制活性，其中7a的抑制活性IC₅₀=52.10（±0.10） nM。

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	刘路显
	周雪琴
	刘东志
	汪天洋
	李巍

关键词： ALK激酶抑制剂嘧啶类合成抗肿瘤

Abstract： Structural modification of NVP-TAE684 was based on the reported ALK kinase inhibitor. Compound 1 was introduced into the nitrogen heterocycle pyrazine by amination to obtain compound 2, Boc group was then removed to give amine intermediates (3). Two pyrazine modified pyrimidine derivatives (7a, 7b) were finally obtained through palladium-catalyzed C-N coupling reactions of compound 3 (3a, 3b) and electrophilic reagent 6. Intermediates 2, 3 and the target compounds 7 have not been reported in other literature. The structures of all six novel compounds have been characterized by ¹H NMR, ¹³C NMR and HRMS-ESI. MTT method was employed to investigate the in vitro inhibition activities of 7a or 7b against non-small cell lung cancer NCI-H460 and NCI-H520. The results indicate that 7a and 7b show good inhibition activities and 7a shows the IC₅₀ value of 52.10±0.10 nM against NCI-H460.

Keywords： ALK kinase inhibitors； pyrimidine； synthesis； antitumor activity

Received 2019-05-20;

Fund:国家自然科学基金资助项目（21576195和21776207）。

Corresponding Authors: 李巍,E-mail:liwei2008@tju.edu.cn。 Email: liwei2008@tju.edu.cn

About author: 刘路显(1992-),女,硕士研究生,主要从事精细有机合成研究。

引用本文:

刘路显, 周雪琴, 刘东志, 汪天洋, 李巍.新型嘧啶类化合物的合成及抗肿瘤活性[J]. 化学工业与工程, 2020,37(3): 31-38

Liu Luxian, Zhou Xueqin, Liu Dongzhi, Wang Tianyang, Li Wei.Synthesis and Antitumor Activities of Novel Pyrimidine Derivatives[J]. Chemcial Industry and Engineering, 2020,37(3): 31-38

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