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

作　　者：曹阳 李前 王亚玲 崔文慧 钱晨亮 司鑫鑫 CAO Yang;LI Qian;WANG Ya-ling;CUI Wen-hui;QIAN Chen-liang;SI Xin-xin(School of Chemistry and Chemical Engineering,Nanjing University,Nanjing 210093,China;Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,Jiangsu Ocean University,Lianyungang 222005,China)

机构地区：[1]南京大学化学化工学院,江苏南京210093 [2]江苏海洋大学,江苏省海洋药物活性分子筛选重点实验室,江苏连云港222005

出　　处：《药学学报》2024年第10期2828-2835,共8页Acta Pharmaceutica Sinica

基　　金：江苏海洋大学研究生科研与实践创新计划项目(KYCX2022-31);中国博士后科学基金(2023M741444)。

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(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.

关 键 词：6-氮杂吲哚 抗胰腺癌 双特异性酪氨酸磷酸化调控激酶1A 合成 抗增殖 

分 类 号：R914[医药卫生—药物化学]