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

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(IC_(50)=6.40±0.34μmol·L^(-1))和Ⅱ-2(IC_(50)=7.15±0.51μmol·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。

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(IC_(50)=6.40±0.34μmol·L^(-1))andⅡ-2(IC_(50)=7.15±0.51μmol·L^(-1))exhibited outstanding activity.Subsequently,the anti-migration ability and invasion ability ofⅡ-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 ofⅡ-1 andⅡ-2 was 48%and 32%,respectively.