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刘晓飞, 王庭芳, 鞠曹云, 张灿. 4-苯基-吡咯并［2,3-d］嘧啶类JAK2激酶抑制剂的设计、合成和抗肿瘤活性[J]. 中国药科大学学报, 2017, 48(2): 150-156. DOI: 10.11665/j.issn.1000-5048.20170204
引用本文: 刘晓飞, 王庭芳, 鞠曹云, 张灿. 4-苯基-吡咯并［2,3-d］嘧啶类JAK2激酶抑制剂的设计、合成和抗肿瘤活性[J]. 中国药科大学学报, 2017, 48(2): 150-156. DOI: 10.11665/j.issn.1000-5048.20170204
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LIU Xiaofei, WANG Tingfang, JU Caoyun, ZHANG Can. Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives[J]. Journal of China Pharmaceutical University, 2017, 48(2): 150-156. DOI: 10.11665/j.issn.1000-5048.20170204
Citation: LIU Xiaofei, WANG Tingfang, JU Caoyun, ZHANG Can. Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives[J]. Journal of China Pharmaceutical University, 2017, 48(2): 150-156. DOI: 10.11665/j.issn.1000-5048.20170204
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4-苯基-吡咯并［2,3-d］嘧啶类JAK2激酶抑制剂的设计、合成和抗肿瘤活性

Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives

    摘要
  • 摘要: 以JAK2激酶抑制剂鲁索替尼(ruxolitinib)为先导化合物，应用分子杂交的药物设计原理，通过结构修饰改造，设计、合成了一系列新的4-苯基-吡咯并［2，3-d］嘧啶类衍生物并进行初步的体外活性评价。以4，6-二羟基嘧啶为起始原料，依次通过Vilsmeier-Haack反应、SNAr取代、成环、脱水、Suzuki偶联、酰基化等多步反应最终合成得到12个目标化合物( 12a ~ 12l )，其结构经1H NMR、13C NMR、HRMS确证。对目标化合物进行体外JAK2激酶活性、GM-CSF诱导的TF-1细胞活性测试，结果表明，部分化合物( 12b 、 12e 和 12h )具有一定程度的JAK2抑制活性；采用MTT法测试目标化合物对JAK2非依赖性A549细胞的抗增殖能力，结果显示，该类化合物A549细胞表现出良好的增殖抑制活性，尤其是化合物 12c (IC50=0.12 μmol/L)活性最强，表明该类化合物具有潜在的研究开发价值。

     

    Abstract: A series of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives were synthesized through modifying the structure of the lead compound ruxolitinib by molecular hybridization strategy. It was synthesized from pyrimidine-4, 6-diol by Vilsmeier-Haack reaction, SNAr reaction, cyclized, dehydration, Suzuki coupling and finally acylated to give 12 new compounds( 12a - 12l ). All structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, and HRMS analysis. The biological activities were evaluated in vitro. Their JAK2 inhibitory activities were studied using JAK2 enzymatic and TF1-GMCSF cellular assays. The results indicated that compounds 12b , 12e and 12h showed moderate activity. The anti-tumor activities were studied against JAK2-independent A549 cell line by the MTT assay. Results showed that the title compounds exhibited potent antiproliferative effect on A549, especially compound 12c (IC50=0. 12 μmol/L), suggesting that this series compounds might be promising anti-tumor agents for futher investigation.

     

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