基于反式-β-芳基烯丙酰四氢异喹啉母核的HDAC抑制剂:设计、合成及其抗肿瘤活性研究  

Structurally novel HDAC inhibitors based on the trans-β-arylacryl tetrahydroisoquinoline scaffold:the design,synthesis,and anticancer activity

作　　者：高鑫 韩维维 田诗意 方方 马晓东 柴化怡 韩京晶 GAO Xin;HAN Wei-wei;TIAN Shi-yi;FANG Fang;MA Xiao-dong;CHAI Hua-yi;HAN Jing-jing(College of Pharmacy,Anhui University of Chinese Medicine,Hefei 230012,China;Department of Medicinal Chemistry,Anhui Academy of Chinese Medicine,Hefei 230012,China;Anhui Province Key Laboratory of Research&Development of Chinese Medicine,Hefei 230012,China)

机构地区：[1]安徽中医药大学药学院,安徽合肥230012 [2]安徽省中医药科学院药物化学研究所,安徽合肥230012 [3]中药研究与开发安徽省重点实验室,安徽合肥230012

出　　处：《药学学报》2023年第2期413-422,共10页Acta Pharmaceutica Sinica

基　　金：安徽省高等学校自然科学研究重点项目资助(KJ2019A1004).

摘　　要：本研究基于前期获得的抗肿瘤反式-β-芳基烯丙酰四氢异喹啉骨架,设计合成了18个HDAC抑制剂(histone deacetylases inhibitors,HDACis),并对其进行抗肿瘤活性评价。体外抑酶活性测试结果表明,化合物13d~13f、13m~13o呈现出优异的HDAC1抑制活性,IC_(50)在个位数纳摩尔或亚纳摩尔级。体外抗增殖实验结果表明,13o表现出显著的抗增殖活性(A549,IC_(50)=0.89μmol·L^(-1);HCT116,IC_(50)=0.49μmol·L^(-1)),优于阳性对照vorinostat(SAHA);此外,对HDAC1抑制活性最强的13e(IC_(50)=3.8 nmol·L^(-1))亦呈现出优良的抗增殖活性(A549,IC_(50)=1.74μmol·L^(-1);HCT116,IC_(50)=2.43μmol·L^(-1))。Western blot实验表明,化合物13e可剂量依赖性地上调A549细胞内组蛋白H3和α-tubulin的乙酰化水平。这些结果表明,化合物13e和13o具有进一步研究价值。In this study,a series of 18 histone deacetylases inhibitors(HDACis),derived from our in-house anti-cancer trans-β-arylacryl 1,2,3,4-tetrahydroisoquinoline-based scaffold,were designed,synthesized,and antitumor evaluated.HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC_(50)at single-digit nanomolar or subnanomolar level.In addition,13o exerted superior anti-proliferative activity(A549,IC_(50)=0.89μmol·L^(-1);HCT116,IC_(50)=0.49μmol·L^(-1))to that of vorinostat(SAHA).Besides,13e,with the most potent HDAC1 enzymatic activity(IC_(50)=3.8 nmol·L^(-1)),also displayed attractive cellular activity(A549,IC_(50)=1.74μmol·L^(-1);HCT116,IC_(50)=2.43μmol·L^(-1)).The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 andα-tubulin in a dose-dependent manner in A549 cells.In summary,13e and 13o deserve further functional investigation.

关 键 词：HDAC抑制剂 四氢异喹啉 反式-β-芳基烯丙酰基 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]