Synthesis, biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors
Synthesis, biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors
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新型CETP抑制剂熊果酸3β-酯衍生物的合成、生物学评价及SAR研究
DOI：
10.1016/j.bmcl.2019.126824
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发表时间：
2020-01-15
影响因子：
2.7
通讯作者：
Chen, Dongyin
中科院分区：
文献类型：
--
作者：
Chen, Chao;Sun, Renhua;Chen, Dongyin
胆固醇酯转移蛋白(CETP)通过降低人血浆低密度脂蛋白胆固醇水平和升高高密度脂蛋白胆固醇水平，成为防治心血管疾病的有效靶点。本论文设计、合成了一系列熊果酸-3-β-酯类化合物，并对其进行了CETP抑制活性评价。其中活性最强的化合物为U12，酶促IC50值为2.4µM。对接研究表明，分子骨架两端的羧基与CETP活性中心区域的几个极性残基(如Ser191、Cys13和Ser230)之间可能存在的氢键相互作用可显著增强其抑制活性。本研究为这些五环三萜类3β-酯类化合物与CETP蛋白的相互作用提供了结构上的见解，为进一步的修饰和优化奠定了基础。
Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3 beta-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC50 value of 2.4 mu M in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic tri-terpenoid 3 beta-ester derivatives and CETP protein for the further modification and optimization.