Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives

doi:10.6023/cjoc201805005

Chin. J. Org. Chem. ›› 2018, Vol. 38 ›› Issue (12): 3270-3277.DOI: 10.6023/cjoc201805005 Previous Articles Next Articles

Articles

吡咯并三嗪衍生物的合成及其对肿瘤细胞增殖的抑制活性

张娅玲, 马沙沙, 李夏冰, 侯巧丽, 吕梦娇, 郝云霞, 王伟, 李宝林

陕西师范大学化学化工学院教育部药用资源与天然药物化学重点实验室西北濒危药材资源开发国家工程实验室西安 710062

收稿日期:2018-05-02 修回日期:2018-06-18 发布日期:2018-08-22
通讯作者: 李夏冰, 李宝林 E-mail:xiabingli@snnu.edu.cn;baolinli@snnu.edu.cn
基金资助:
国家自然科学基金（No.21272144）及中央高校基本科研业务费专项资金（Nos.GK201603034，GK201706005，X2015YB06）资助项目.

Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives

Zhang Yaling, Ma Shasha, Li Xiabing, Hou Qiaoli, Lü Mengjiao, Hao Yunxia, Wang Wei, Li Baolin

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710062

Received:2018-05-02 Revised:2018-06-18 Published:2018-08-22
Contact: 10.6023/cjoc201805005 E-mail:xiabingli@snnu.edu.cn;baolinli@snnu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (No. 21272144) and the Fundamental Research Funds for the Central Universities (Nos. GK201603034, GK201706005, X2015YB06).

1. Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives.PDF(5671KB)

Abstract

In order to find novel antitumor agents with high efficiency and low toxicity, 11 novel pyrrolo[2,1-f] [1,2,4]triazine derivatives were designed and synthesized through the introduction of varied structural moieties to the 4,6-positions of pyrrolotriazine core. The antiproliferative activities of synthesized compounds were also evaluated against human tumor cells. Firstly, 2-amino-2-cyanoacetamide (1) was prepared from methyl cyanoacetate as a starting material through three step reactions of oximation, reduction and ammonolysis. Meanwhile, ethyl 2-acetyl-3-(dimethylamino)acrylate (2) was obtained from the reaction of ethyl acetoacetate with N,N-dimethylformamide dimethyl acetal. Then the cyclization reaction of 1 with 2 gave ethyl 5-cyano-4-methylpyrrole-3-carboxylate (4). Finally, pyrrolotriazine derivatives as target compounds were synthesized from 4 through the ammoniation, generating amidine, Dimroth rearrangement, and subsequent hydrolyzation and acylation. The antiproliferative activities of target compounds against human tumor cell lines were investigated by methyl thiazolyl tetrazolium (MTT) colorimetric assay. The results demonstrated that most synthesized compounds had obviously selective inhibitory effects against A431 cells with highly expressed wild type epidermal growth factor receptor (EGFR). Ethyl 4-(3-ethynylphenylamino)-5-methylpyrrolo[2,1-f] [1,2,4]triazine-6-carboxylate (7c), 4-(3-chloro-4-(3-fluorobenzyloxy)phenyl-amino)-5-methylpyrrolo[2,1-f] [1,2,4]triazine-6-carboxylic acid (8a) and 4-(3-ethynylphenylamino)-5-methylpyrrolo[2,1-f]-[1,2,4]triazine-6-(N-(2-(methylsulfonyl)ethyl))carboxamide (9c) were the most potent agents with IC₅₀ values of 20.05, 21.98 and 23.87 μmol·L^-1 in the synthesized compounds, respectively. Preliminary structure-activity relationship analysis indicated that the introduction of 3-chloro-4-(3-fluorobenzyloxy)phenylamino and 3-ethynylphenylamino to 4-position of pyrrolotriazine-6-carboxylic acids or its esters can lead to enhance antiproliferative activities against A431 tumour cells.

Key words: pyrrolotriazine, 4-arylaminopyrrolotriazine, Dimroth rearrangement, tumor, antiproliferative activity

Cite this article

Zhang Yaling, Ma Shasha, Li Xiabing, Hou Qiaoli, Lü Mengjiao, Hao Yunxia, Wang Wei, Li Baolin. Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives[J]. Chin. J. Org. Chem., 2018, 38(12): 3270-3277.

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吡咯并三嗪衍生物的合成及其对肿瘤细胞增殖的抑制活性

Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives

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