Ren Yulin, Himmeldirk Klaus, Chen Xiaozhuo
Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701, USA.
J Med Chem. 2006 May 4;49(9):2829-37. doi: 10.1021/jm060087k.
The rapid increase of obesity-associated diabetes has created urgent demands for more effective antidiabetic therapies and pharmaceuticals that are able to address the problems of hyperglycemia and weight gain simultaneously. Our previous studies indicated that the alpha- and beta-anomers of penta-O-galloyl-D-glucopyranose (PGG), 2 and 3, act as insulin mimetics that bind to and activate the insulin receptor, stimulate glucose transport in adipocytes, and reduce blood glucose and insulin levels in diabetic and obese animals. In addition, they inhibit differentiation of preadipocytes into adipocytes. These activities suggest that 2 and 3 may reduce blood glucose without increasing adiposity. To investigate the structure-activity relationship of 2 and 3, four series of novel compounds were prepared and their glucose transport stimulatory activities were measured using a radioactive glucose uptake bioassay. The assay results indicate that both the glucose and the galloyl groups are critical to the activity of 2 and 3. It appears that the glucose core provides an optimal scaffold to present the galloyl groups with the correct spatial orientation to induce activity. Moreover, the galloyl groups linked to the 1, 2, 3, and 4 positions of glucose are essential, while the galloyl group connected to the 6 position of 2 is unnecessary for the induction of activity. The discovery that two related novel compounds, 6-deoxytetra-O-galloyl-alpha-D-glucopyranose (43) and tetra-O-galloyl-alpha-D-xylopyranose (59), also possess glucose transport stimulatory activity suggests that 2 may be further modified around position 6 to modulate and enhance its efficacy. To test this hypothesis, we developed a new synthetic method that allows for the stereoselective preparation of derivatives of 2 that are modified on C-6. We found that 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-alpha-D-glucopyranose (80) exhibits a significantly higher glucose transport stimulatory activity than 2. Its activity is comparable to that of insulin.
肥胖相关糖尿病的迅速增加，迫切需要更有效的抗糖尿病疗法和药物，以同时解决高血糖和体重增加的问题。我们之前的研究表明，五-O-没食子酰-D-吡喃葡萄糖（PGG）的α-和β-端基异构体2和3可作为胰岛素模拟物，与胰岛素受体结合并激活该受体，刺激脂肪细胞中的葡萄糖转运，并降低糖尿病和肥胖动物的血糖和胰岛素水平。此外，它们还能抑制前脂肪细胞向脂肪细胞的分化。这些活性表明2和3可能在不增加肥胖的情况下降低血糖。为了研究2和3的构效关系，我们制备了四个系列的新型化合物，并使用放射性葡萄糖摄取生物测定法测量了它们的葡萄糖转运刺激活性。测定结果表明，葡萄糖和没食子酰基对2和3的活性都至关重要。似乎葡萄糖核心提供了一个最佳支架，以使没食子酰基以正确的空间取向呈现以诱导活性。此外，连接到葡萄糖1、2、3和4位的没食子酰基是必不可少的，而连接到2的6位的没食子酰基对于诱导活性则是不必要的。两个相关的新型化合物6-脱氧四-O-没食子酰-α-D-吡喃葡萄糖（43）和四-O-没食子酰-α-D-吡喃木糖（59）也具有葡萄糖转运刺激活性，这一发现表明2可能在6位周围进一步修饰以调节和增强其功效。为了验证这一假设，我们开发了一种新的合成方法，该方法允许立体选择性地制备在C-6位修饰的2的衍生物。我们发现6-氯-6-脱氧-1,2,3,4-四-O-没食子酰-α-D-吡喃葡萄糖（80）表现出比2显著更高的葡萄糖转运刺激活性。其活性与胰岛素相当。
