石胆酸类似物的设计、合成及其蛋白酪氨酸磷酸酯酶1B抑制活性
收稿日期: 2016-05-12
修回日期: 2016-05-27
网络出版日期: 2016-07-13
基金资助
江苏省自然科学基金青年（No.BK20140425）及南通大学引进人才科研启动费（No.03080694）资助项目.
Design, Synthesis of Lithocholic Acid Mimics and Their Inhibitory Activities against Protein Tyrosine Phosphatase 1B
Received date: 2016-05-12
Revised date: 2016-05-27
Online published: 2016-07-13
Supported by
Project supported by the Science Fund for Young Scholar of Jiangsu Province (No.BK20140425) and the Initiating Fund for Introduced Talents of Nantong University (No.03080694).
蛋白酪氨酸磷酸酯酶1B（PTP1B）是体内胰岛素信号通路的负调控因子，被视为治疗糖尿病的潜在靶标.甾体类天然产物石胆酸3（LCA）具有较好的PTP1B抑制活性.为了提供石胆酸衍生合成多样性的基本骨架，并探讨甾环上特定位点（3，4，5，6及23位）取代基及其构型与PTP1B抑制活性的关系，设计并合成了一组石胆酸类似物.PTP1B抑制活性测试结果显示，3β-羟基胆烷-4-烯酸（17）和4，4-二甲基-3β-羟基-5-烯-胆烷酸（19）对PTP1B的抑制活性均比石胆酸有所提高，分别达到（8.50±1.21）和（6.27±1.03）μmol·L-1.此外，通过计算机模拟对接阐明了两个化合物与酶的可能结合方式.为进一步研究PTP1B抑制剂提供了新的骨架化合物及有价值的构效关系信息.
何海兵 , 戴红 , 高立信 , 张海军 , 邹政 , 杨帆 , 李佳 , 石玉军 . 石胆酸类似物的设计、合成及其蛋白酪氨酸磷酸酯酶1B抑制活性[J]. 有机化学, 2016 , 36(11) : 2670 -2676 . DOI: 10.6023/cjoc201605018
Protein tyrosine phosphatase-1B (PTP1B), a negative regulatory factor of insulin signaling, is recognized as a potent target for the therapy of diabetes. Aimed to provide new scaffold to the development of PTP1B inhibitors and disclose the relationship between configurations of certain positions (3, 4, 5, 6 and 23-position) on the steroidal skeleton and inhibitory activities against PTP1B, a class of lithocholic acid (LCA) mimics were designed and synthesized. In vitro bioassay against PTP1B showed that 3β-hydroxy-4-ene-cholanic acid (17) and 4,4-dimethyl-3β-hydroxy-5-ene-cholanic acid (19) had activities higher than LCA, reaching (8.50±1.21) and (6.27±1.03) μmol·L-1, respectively. Docking analysis of compounds 17 and 19 illuminated the binding modes to PTP1B. This study provided compounds with new scaffold and valuable structure-activity-relationship (SAR) information for the further study of PTP1B inhibitors.
Key words： PTP1B inhibitor; steroid; lithocholic acid mimics; synthesis
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