基于Rucaparib的新型PARP1降解剂的设计、合成及生物活性研究  

Design,synthesis and bioactivity study of the novel PARP1 degraders based on rucaparib

作　　者：刘全裕 邹艳辉 黄镇良 陈文倩 黄欣 陈彧婷 LIU Quanyu;ZOU Yanhui;HUANG Zhenliang;CHEN Wenqian;HUANG Xin;CHEN Yuting(Department of Pharmacy,Fujian Health College,Fuzhou 350101,China)

机构地区：[1]福建卫生职业技术学院药学院,福建福州350101

出　　处：《中国药物化学杂志》2024年第5期361-368,共8页Chinese Journal of Medicinal Chemistry

基　　金：福建卫生职业技术学院高层次人才科研启动专项(MWY2023-5-03);福建卫生职业技术学院青年科研项目(MWY2022-1-01);福建省中青年教师教育科研项目(JZ180549)。

摘　　要：目的基于PROTAC原理以rucaparib为PARP1配体,设计、合成可降解PARP1蛋白的新型降解剂,以期开发新型抗肿瘤药物。方法将PARP1抑制剂rucaparib与E3连接酶配体泊马度胺通过不同的中间链进行连接,经化学合成获得目标化合物。利用Western blot研究目标化合物降解蛋白的活性与机制,并以人乳腺癌MCF-7、MDA-MB-231细胞为测试细胞株,对所合成的目标化合物进行体外抗肿瘤活性筛选。结果与结论设计并合成了7个未见文献报道的靶向PARP1的降解剂,其结构经质谱和核磁共振谱确证。其中化合物RP0、RPP3以及RPP5均具有PARP1降解活性,且RP0对PARP1的降解通过泛素蛋白酶体途径实现,值得进一步研究。Based on the principle of PROTAC,seven novel PARP1 degraders were designed and synthesized to develop new antitumor drugs.The PARP1 inhibitor rucaparib and the E3 ligase ligand pomalidomide were linked by different intermediate chains to obtain the target compounds.The target compounds were characterized by MS and NMR.Western blot was used to examine the degradation activity and mechanism of the target compounds.MTT assay was used to evaluate the anti-proliferation effect of compounds in human breast cancer MCF-7 and MDA-MB-231 cells.The Western blot results showed that compounds RPO,RPP3 and RPP5 have PARP1 degradation activity,and RPO induces degradation of PARP1 through the ubiquitinproteasome pathway,which deserves further investigation.

关 键 词：rucaparib PARP1 PROTAC 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]