摘要/Abstract

蛋白酪氨酸磷酸酶1B （PTP1B）作为胰岛素和瘦素信号转导通路的负调节因子，PTP1B抑制剂有希望成为治疗Ⅱ型糖尿病和肥胖症的候选药物.为了寻找非酸类PTP1B抑制剂，设计、合成了一系列含1H-苯并[d]咪唑或1H-苯并[d][1，2，3]三唑的查尔酮类化合物，并对化合物进行了PTP1B抑制活性测定.结果显示，所有化合物对PTP1B均显示出较强的抑制活性，其中2-（1H-苯并[d][1，2，3]三唑-1-基）-N'-（4-（3-（2'-萘基）-3-氧亚基-丙-1-烯基）苯亚甲基）乙酰肼（10i）活性最佳，IC₅₀为（2.98±0.04）μmol·L^-1.更重要的是，2-（1H-苯并[d][1，2，3]三唑-1-基）-N'-（4-（3-（4-甲基苯基）-3-氧亚基-丙-1-烯基）苯亚甲基）乙酰肼（10h）在20 μg/mL的浓度下对T细胞蛋白酪氨酸磷酸酶（TCPTP）没有活性，显示了较好的选择性.
关键词: PTP1B抑制剂, 1H-苯并[d]咪唑, 1H-苯并[d] [1,2,3]三唑, 查尔酮
Protein tyrosine phosphatase 1B (PTP1B) inhibitor has recently been identified as new candidate drug for type Ⅱ diabetes and obesity due to it is a negative regulator of the insulin and leptin-signaling pathway. In order to find new nonphosphonate-based pTyr mimetics, a series of novel chalcone derivatives bearing 1H-benzo[d]imidazol or 1H-benzo[d] [1,2,3]-triazol moieties were designed, synthesized, and evaluated for their PTP1B inhibitory activities. The results demonstrated that all compounds presented potent inhibitory activities against PTP1B, among which 2-(1H-benzo[d] [1,2,3]triazol-1-yl)-N'-(4-(3-(naphthalen-2-yl)-3-oxoprop-1-en-1-yl)benzylidene)acetohydrazide (10i) exhibited the best potency with IC₅₀ value of (2.98±0.04) μmol·L^-1. Importantly, 2-(1H-benzo[d] [1,2,3]triazol-1-yl)-N'-(4-(3-oxo-3-(p-tolyl)prop-1-en-1-yl)benzylidene)-acetohydrazide (10h) showed no significant inhibition on T-cell protein tyrosine phosphatase (TCPTP) at the concentration of 20 μg/mL, suggesting the highly selectivity of this agent toward PTP1B.
Key words: PTP1B inhibitor, 1H-benzo[d]imidazol, 1H-benzo[d] [1,2,3]triazol, chalcone


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