有机化学 ›› 2016, Vol. 36 ›› Issue (11): 2670-2676.DOI: 10.6023/cjoc201605018 上一篇    下一篇

研究论文

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

何海兵a, 戴红a, 高立信b, 张海军a, 邹政a, 杨帆c, 李佳b, 石玉军a   

  1. a 南通大学化学化工学院 南通 226019;
    b 中国科学院上海药物研究所 国家新药筛选中心 上海 201203;
    c 华东师范大学化学与分子工程学院 上海分子治疗与新药创制工程技术中心 上海 200062
  • 收稿日期:2016-05-12 修回日期:2016-05-27 发布日期:2016-07-13
  • 通讯作者: 杨帆, 石玉军 E-mail:fyang@chem.ecnu.edu.cn;shyj123123@163.com
  • 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

He Haibinga, Dai Honga, Gao Lixinb, Zhang Haijuna, Zou Zhengaa, Yang Fanc, Li Jiab, Shi Yujuna   

  1. a College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019;
    b National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203;
    c Shanghai Engineering Institute of Molecular Therapy and Medicinal Development(MTDD), School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062
  • Received:2016-05-12 Revised:2016-05-27 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.

关键词: PTP1B抑制剂, 甾体, 石胆酸类似物, 合成

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