化合物E0869体外抗动脉粥样硬化的活性研究  

The in vitro anti-atherosclerotic activity of compound E0869

作　　者：王潇 刘畅 刘鹏 李霓 许艳妮 司书毅 

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所国家新药微生物筛选实验室,北京100050

出　　处：《药学学报》2015年第4期440-446,共7页Acta Pharmaceutica Sinica

基　　金：国家“重大新药创制”科技重大专项资助项目(2012ZX09301002-001);国家自然科学基金资助项目(81102443);国家自然科学基金面上项目(81273515);北京协和医学院“青年基金教师项目”(3332013089);北京协和医学院“青年基金学生项目”(33320140155)

摘　　要：ATP结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)和清道夫受体B型I(scavenger receptor class B type I,SR-BI/CLA-1)是胆固醇逆转运过程中的重要蛋白。ABCA1和SR-BI/CLA-1的高表达能降低动脉粥样硬化的危险性。因此,本研究利用前期已建立的人ABCA1和CLA-1表达上调剂筛选模型,对20 000个化合物进行筛选,获得能上调ABCA1和CLA-1表达的化合物E0869[4-甲磺酰甲基苯甲酸-1-(3,4-二甲基苯基)-1-丙酮-2-酯],其上调活性分别为160%和175%,EC50值分别为3.79和1.42μmol·L-1;进一步研究发现,活性化合物E0869能上调肝细胞Hep G2以及巨噬细胞RAW264.7中ABCA1、SR-BI/CLA-1以及ABCG1的m RNA和蛋白水平,但不影响FAS、SREBP-1c、CD36的表达;E0869能使泡沫化巨噬细胞RAW264.7胞内脂滴量明显减少,并能增加其胆固醇的流出。因此,化合物E0869能够上调ABCA1和CLA-1活性,并且具有较好的体外抗动脉粥样硬化效果。ATP-binding cassette transporter A1（ABCA1） and scavenger receptor class B type I（SR-BI/ CLA-1） are the key proteins in reverse cholesterol transport（RCT）. The high expression of ABCA1 and SR-BI/ CLA-1 can decrease the danger of atherosclerosis. The purpose of the study is to find ABCA1 and CLA-1 up-regulators for treating atherosclerosis by using cell-based high throughput screening models. Among 20 000 compounds screened, E0869 [1-（3, 4-dimethylphenyl）-1-oxopropan-2-yl 4-（（methylsulfonyl）methyl）benzoate] was found as the positive hit. The up-regulated activities of E0869 in ABCA1p-LUC and CLA-1p-LUC Hep G2 cell were 160% and 175%, respectively. The EC50 values of E0869 in ABCA1p-LUC and CLA-1p-LUC Hep G2 cell were 3.79 and 1.42 μmol·L-1, respectively. E0869 could upregulate the m RNA and protein levels of ABCA1, SR-BI/CLA-1 and ABCG1 genes in Hep G2 and RAW264.7 cells by Real-Time Quantitative PCR and Western blotting analysis, but could not influence the expression of FAS, SREBP-1c and CD36. Foam cell assay showed that E0869 could inhibit lipids accumulation in mouse peritoneal macrophages RAW264.7. Cholesterol efflux assay showed that E0869 could induce HDL-mediated cholesterol efflux in mouse peritoneal macrophages RAW264.7. In conclusion, E0869 could up-regulate ABCA1 and CLA-1 activity, and had good anti-atherosclerotic activity in vitro.

关 键 词：4-甲磺酰甲基苯甲酸-1-(3 4-二甲基苯基)-1-丙酮-2-酯 ATP结合盒转运体 清道夫受体B型I 动脉粥样硬化 

分 类 号：R963[医药卫生—微生物与生化药学]