Citation: 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 shu

Synthesis and Antiproliferative Activities of Novel Pyrrolotriazine Derivatives

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

Corresponding author: Li Xiabing, xiabingli@snnu.edu.cn Li Baolin, baolinli@snnu.edu.cn
Received Date: 2 May 2018
Revised Date: 18 June 2018
Available Online: 22 December 2018
Fund Project: the Fundamental Research Funds for the Central Universities GK201706005Project supported by the National Natural Science Foundation of China (No. 21272144) and the Fundamental Research Funds for the Central Universities (Nos. GK201603034, GK201706005, X2015YB06)the Fundamental Research Funds for the Central Universities X2015YB06the National Natural Science Foundation of China 21272144the Fundamental Research Funds for the Central Universities GK201603034

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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.
- pyrrolotriazine,
- 4-arylaminopyrrolotriazine,
- Dimroth rearrangement,
- tumor,
- antiproliferative activity
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