Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor
Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor
复制标题
小檗碱类似物作为低密度脂蛋白受体和胰岛素受体新型上调剂的合成和生物学评价
DOI：
10.1016/j.bmcl.2009.09.059
复制
发表时间：
2009-11-01
影响因子：
2.7
通讯作者：
Song, Dan-Qing
中科院分区：
文献类型：
--
作者：
Wang, Yan-Xiang;Wang, Yu-Ping;Song, Dan-Qing
小檗碱（BBR）是一种天然化合物，对低密度脂蛋白受体（LDLR）和胰岛素受体（InsR）均有上调作用。这种一药多靶点的特点可能适用于代谢综合征的治疗。在寻找对LDLR和InsR表达均有效的上调剂时，对BBR类似物进行了结构-活性关系（SAR）分析。设计、合成了14个BBR类似物，并进行了生物学评价。SAR分析表明，适当的modi。BBR苯环A或D上的阳离子可能保留了对LDLR和InsR表达的上调活性。在这些化合物中，在D环上带有9-甲氧基和10-羟基的化合物13 a显示出对LDLR或InsR基因表达的有希望的活性。13 a的10-羟基可能是连接适当化学基团的臂，以优化药物的体内生物利用度。因此，13 a可以被认为是制备用于血脂或葡萄糖的前药的母体化合物。(C)2009爱思唯尔有限公司保留所有权利。
Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. In searching for up-regulators effective for both LDLR and InsR expression, the structure-activity relationship (SAR) analysis for BBR analogues was done. Fourteen BBR analogues were designed, synthesized and biologically evaluated. SAR analysis revealed that appropriate modi. cations on the phenyl ring A or D of BBR might retain the up-regulatory activities on the expression of both LDLR and InsR. Among these compounds, compound 13a bearing 9-methoxy and 10-hydroxyl on the ring D showed promising activities on either LDLR or InsR gene expression. The 10-hydroxyl of 13a could be an arm to connect proper chemical groups for optimizing drug-bioavailability in vivo. Thus, 13a could be considered to be a parent compound to make pro-drugs for either blood lipids or glucose. (C) 2009 Elsevier Ltd. All rights reserved.