摘要
目的发现新型抗动脉粥样硬化药物的先导化合物,并进行体外抗动脉粥样硬化活性研究。方法应用ABCA1和CLA-1表达上调剂筛选模型,对2000个化合物进行筛选,获得能上调ABCA1和CLA-1表达的化合物;利用RT-PCR和Westernblot方法研究化合物对目的蛋白的作用;利用巨噬细胞泡沫化实验测定化合物的体外抗动脉粥样硬化作用。结果 5242331在ABCA1和CLA-1上调剂模型上的EC50值分别为1.66和3.00μmol/L;进一步研究发现,5242331不仅能上调肝细胞HepG2中CLA-1的mRNA以及蛋白水平,还能上调巨噬细胞RAW264.7中ABCA1和SR-BI的mRNA以及蛋白水平;5242331能明显减少泡沫化巨噬细胞RAW264.7胞内脂滴量。结论化合物5242331具有较好上调ABCA1和CLA-1活性和较好的体外抗动脉粥样硬化效果,属首次报道。
Objective The study was designed to find new anti-atherosclerotic leading compounds targeting human ATP-binding cassette transporter A1 （ABCAI） and scavenger receptor class B type I （SR-BI）, and then study the anti-atherosclerotic activity of the compounds in vitro. Methods Using ABCA1 and CLA-1 cell-based high throughput screening models, 2000 compounds were screened to find new anti-atherosclerotic compound. RT- PCR and Western blot were used to evaluate the effects of compounds on ABCA1 and SR-BI/CLA-1 expressions in HepG2 and RAW264.7. Foam cell assay was performed to examine the anti-atherosclerotic activity of the compound. Results The ECs0 values of 5242331 in ABCAlp-LUC and CLA-lp-LUC HepG2 cell were 1.66 and 3.00 pmol/L, respectively. 5242331 could significantly up-regulate CLA-1 expression in HepG2 cells, and also up-regulate ABCA1 and CLA-1 expressions in RAW264.7. In addition, foam cell assay showed that 5242331 could significantly inhibit lipid accumulation in RAW264.7. Conclusion This is first reported that 5242331 could up-regulate ABCA1 and CLA-1 activity, and had good anti-atherosclerotic activity in vitro.
出处
《中国抗生素杂志》
CAS
CSCD
北大核心
2013年第6期419-423,共5页
Chinese Journal of Antibiotics
基金
国家自然科学基金面上项目(81273515)
国家自然科学基金(81102443)
