曹阳, 李前, 王亚玲, 崔文慧, 钱晨亮, 司鑫鑫. 6-氮杂吲哚类化合物的合成及抗胰腺癌活性评价J. 药学学报, 2024, 59(10): 2828-2835. DOI: 10.16438/j.0513-4870.2024-0135
引用本文: 曹阳, 李前, 王亚玲, 崔文慧, 钱晨亮, 司鑫鑫. 6-氮杂吲哚类化合物的合成及抗胰腺癌活性评价J. 药学学报, 2024, 59(10): 2828-2835. DOI: 10.16438/j.0513-4870.2024-0135
CAO Yang, LI Qian, WANG Ya-ling, CUI Wen-hui, QIAN Chen-liang, SI Xin-xin. Synthesis and activity evaluation of 6-azazindole derivatives for pancreatic cancer therapyJ. Acta Pharmaceutica Sinica, 2024, 59(10): 2828-2835. DOI: 10.16438/j.0513-4870.2024-0135
Citation: CAO Yang, LI Qian, WANG Ya-ling, CUI Wen-hui, QIAN Chen-liang, SI Xin-xin. Synthesis and activity evaluation of 6-azazindole derivatives for pancreatic cancer therapyJ. Acta Pharmaceutica Sinica, 2024, 59(10): 2828-2835. DOI: 10.16438/j.0513-4870.2024-0135

6-氮杂吲哚类化合物的合成及抗胰腺癌活性评价

Synthesis and activity evaluation of 6-azazindole derivatives for pancreatic cancer therapy

  • 摘要: 通过筛选内部化合物库, 鉴定出了具有一定抗胰腺癌活性的片段。经系统改造合成了4类共计18个化合物, 并进行了抗胰腺癌活性评价。化合物Ⅱ-1 (IC50 = 6.40 ± 0.34 μmol·L-1) 和Ⅱ-2 (IC50 = 7.15 ± 0.51 μmol·L-1) 活性表现突出。随后用细胞划痕实验及侵袭实验评价了Ⅱ-1的抗迁移能力及侵袭能力, 结果显示, Ⅱ-1具有良好的抗迁移能力及突出的抗侵袭能力。利用分子对接技术及分子动力学模拟技术, 锁定了Ⅱ-1的靶点为双特异性酪氨酸磷酸化调控激酶1A (DYRK1A)。经酶活测试Ⅱ-1和Ⅱ-2分别有48%及32%酶抑制能力。

     

    Abstract: Fragment with some anti-pancreatic cancer activity was identified by screening our internal chemical library. Eighteen compounds in 4 classes were synthesized by systematic modification and their anti-pancreatic cancer activity were evaluated. Ⅱ-1 (IC50 = 6.40 ± 0.34 μmol·L-1) and Ⅱ-2 (IC50 = 7.15 ± 0.51 μmol·L-1) exhibited outstanding activity. Subsequently, the anti-migration ability and invasion ability of Ⅱ-1 was evaluated by wound healing assay and invasion assay, Ⅱ-1 exhibited good anti-migration ability and outstanding anti-invasion ability. Using molecular docking technology and molecular dynamics simulation technology, the potential target was locked on bispecific tyrosine phosphorylation regulates kinase 1A (DYRK1A). By enzyme activity testing, the inhibitory capacity of Ⅱ-1 and Ⅱ-2 was 48% and 32%, respectively.

     

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