摘要/Abstract

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


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