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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 is thought to be a potential target for the treatment of atherosclerosis by foaming macrophages by binding and endocytosing oxLDL to form focal sites of atherosclerotic lesions. 13-Hexylberberine (2) showed antagonistic activity on scavenger receptor CD36. In this study, 21 2 analogues were designed and synthesized, and their anti-CD36 activities were determined by ELISA-like high-throughput screening Activity was evaluated. The preliminary structure-activity relationship results show that the introduction of the appropriate groups at the 2nd and 3rd ring positions of A ring or 9th ring of D ring can increase the activity of the compound. Among the 21 analogues, 7g of compound (benzyloxy at the 9-position) showed the highest CD36 antagonistic activity with an IC50 of 7.7μmol·L-1. In addition, 7 g of CD36 antagonistic activity was also validated in another high-throughput screening model. Therefore, berberine derivatives is a new class of CD36 receptor antagonists, worthy of further study.