13-己基小檗碱类似物的合成及CD36拮抗活性的构效关系研究  

Synthesis and structure-activity relationship of 13-hexylberberine analogues as CD36 antagonists

作　　者：李迎红[1] 王丽[1] 洪斌[1] 许艳妮[1] 司书毅[1] 蒋建东[1] 宋丹青[1] 

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,北京100050

出　　处：《药学学报》2010年第9期1128-1133,共6页Acta Pharmaceutica Sinica

基　　金：“重大新药创制”科技重大专项资助项目(2009ZX09301-003);国家自然科学基金资助项目(90813027)

摘　　要：清道夫受体CD36通过结合并内吞氧化低密度脂蛋白(oxLDL)使巨噬细胞泡沫化从而形成动脉粥样硬化的病灶中心,被广泛认为是治疗动脉粥样硬化的潜在靶点。13-己基小檗碱(2)对清道夫受体CD36显示拮抗活性,本研究以其为先导化合物,设计合成了21个2的类似物,应用ELISA-like高通量筛选模型对其CD36拮抗活性进行了评价。初步构效关系结果表明:在A环2和3位或D环9位引入适当的基团均可提高化合物的活性。在21个类似物中,化合物7g(9位为苄氧基)的CD36拮抗活性最高,其IC50为7.7μmol·L-1。此外,7g的CD36拮抗活性也在另一高通量筛选模型中得到了验证。因此,小檗碱衍生物是一类新型的CD36受体拮抗剂,值得进一步研究。Scavenger receptor CD36 could bind and endocytose oxLDL into macrophages which were then differentiated into foam cells that constitute the atherosclerotic lesion core, and was considered to be a potential target to treat atherosclerosis. In the establishment of the compound library of berberine （BBR, 1） analogues, we discovered that 13-hexylberberine （2） showed an antagonistic activity against CD36. Taking 2 as the lead compound, 21 derivatives were synthesized and their antagonistic activities were evaluated via an ELISA-like high-throughput screening （HTS） model. The primary structure-activity relationships were studied. It was indicated that the introduction of suitable groups at the 2-and 3-position of the aromatic ring A or at the 9-position of the aromatic ring D could enhance the activity. Among the 21 studied compounds, 7g bearing a benzyloxyl group at the 9-position provided a highest CD36 antagonistic activity with the IC50 value of 7.7 μmol·L-1. Besides, its antagonistic activity was further verified with Sf9 insect cell HTS model. So berberine analogues are a new family of CD36 receptor antagonists and worthy to be studied further.

关 键 词：13-己基小檗碱 CD36 拮抗活性 构效关系 氧化低密度脂蛋白 

分 类 号：R916[医药卫生—药学]