有机化学 ›› 2019, Vol. 39 ›› Issue (7): 2106-2116.DOI: 10.6023/cjoc201811020 上一篇    下一篇

研究简报

新型石胆酸-3-肟酯衍生物及其蛋白酪氨酸磷酸酯酶1B抑制活性

侍术智a, 梁志鹏b, 孙建勇a, 石玉军a   

  1. a 南通大学化学化工学院 南通 226019;
    b 南通大学分析测试中心 南通 226019
  • 收稿日期:2018-11-14 修回日期:2019-01-08 出版日期:2019-07-25 发布日期:2019-03-08
  • 通讯作者: 石玉军 E-mail:ntushyj@163.com

Novel Ester Derivatives of Lithocolic Acid-3-oxime and Their Inhibitory Activities against Protein Tyrosine Phosphatase 1B

Shi shuzhia, Liang zhipengb, Sun jiangyonga, Shi Yujuna   

  1. a College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019
  • Received:2018-11-14 Revised:2019-01-08 Online:2019-07-25 Published:2019-03-08
  • Contact: 10.6023/cjoc201811020 E-mail:ntushyj@163.com

蛋白酪氨酸磷酸酯酶1B(PTP1B)是治疗糖尿病的潜在靶标.内源性甾体化合物石胆酸具有温和的PTP1B抑制活性.将石胆酸3-OH氧化后,进一步修饰得到含有肉桂酸片段的石胆酸肟酯类衍生物,并通过1H NMR、13C NMR和HRMS鉴定其结构.生物活性筛选结果表明:所得目标化合物多数具有较强的PTP1B抑制活性,其中化合物12b的IC50达到0.79 μmol·L-1,是先导化合物石胆酸活性的15倍左右,同时该化合物对高度同源的T细胞蛋白酪氨酸磷酸酶(TCPTP)的选择性达到4倍左右.

关键词: PTP1B抑制剂, TCPTP, 石胆酸肟, 合成

Protein tyrosine phosphatase-1B (PTP1B) is recognized as a potent target for the therapy of diabetes. Lithocolic acid (LCA), a kind of endogenic steroid, was reported as a moderate PTP1B inhibitor. In this paper, 3-hydroxyl of LCA was oxidized, followed by oximating and splicing with cinnamoyl to afford a novel series of derivatives, which were characterized by 1H NMR, 13C NMR and HRMS spectra. The results of bioassays exhibited that most of the titled compounds were active to PTP1B. Among them, compound 12b, the most potent one, has an IC50 of 0.79 µmol•L-1, about 15-fold more potent than the lead compound. Besides, it also has a selectivity of about 4-fold over T-cell protein tyrosine phosphatase (TCPTP).

Key words: PTP1B Inhibitor, TCPTP, lithocolic acid-3-oxime, Synthesis