Chinese Journal of Organic Chemistry >
Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives
Received date: 2018-05-02
Revised date: 2018-06-18
Online published: 2018-08-22
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).
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.
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]. Chinese Journal of Organic Chemistry, 2018 , 38(12) : 3270 -3277 . DOI: 10.6023/cjoc201805005
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