Synthesis and Biological Evaluation of New α-Glucosidase inhibitors Designated on the Basis of the Structure of Salacinol

Salacinol（1）是一种有效的α-葡萄糖苷酶抑制剂，从Salacia reticulata WIGHT（在僧伽罗语中称为Kotala himbutu）的根和茎的水提取物中分离出来，传统上在斯里兰卡和印度用于治疗糖尿病。通过X-射线晶体学分析等化学和物理化学证据，揭示了它独特的由1-脱氧-4-硫代阿拉伯呋喃糖基阳离子和1 ′-脱氧赤藓糖基-3 ′-硫酸根阴离子组成的螺状内盐结构。本研究合成了3个侧链缺少羟基和/或羟甲基的水杨酸酚类似物（2，3，4）和O-去磺酸水杨酸酚类似物（5），并研究了它们对α-葡萄糖苷酶的抑制活性，其中化合物2，3，4是用1，4-二脱氧-1，4-表硫代-D-阿拉伯糖醇（6a）环硫酸酯开环法合成的。环状硫酸酯，1，3-丙二醇1，3-环状硫酸酯（7），2-O-苄基甘油1，3-环状硫酸酯（8）和4-O-叔-B 关于我们 用于类似物2、3、4的侧链的丁基二甲基甲硅烷基-2-脱氧-L-甘露糖醇1，3-环硫酸酯（9）分别以良好的产率从1，3-丙二醇、甘油和D-葡萄糖衍生。7与6a的偶联反应以61%产率得到所需的2。以类似于用于6a的方式将从7和8获得的偶联产物脱保护，以良好的产率得到3和4。另一方面，1的酸性甲醇解定量地得到5。体外实验检测了它们对肠道α-葡萄糖苷酶的抑制活性。3个简单的类似物（2，3，4）的抑制活性低于1，证明了极性取代基的协同作用对α-葡萄糖苷酶抑制活性的重要性。另一方面，O-α-葡萄糖苷酶类似物5显示出与1相当的有效α-葡萄糖苷酶抑制活性，并且发现1的硫酸根阴离子部分对于抑制活性不是必需的。化合物5也是通过使用环氧化物（2 R，3S）-1，2-环氧-3，4-双（苄氧基）丁烷（10）与O-苄基化硫代糖6 b的偶联反应合成的，该环氧化物容易从D-异抗坏血酸获得。偶联产物的氢解以良好的产率得到5。少

Salacinol (1)is a potent α-glucosidase inhibitor isolated from the aqueous extracts of the roots and stems of Salacia reticulata WIGHT (known as Kotala himbutu in Singhalese), which is traditionally used in Sri Lanka and India for the treatment of diabetes. Its unique spiro-like structure of the inner salt comprised of 1-deoxy-4-thioarabinofuranosyl cation and 1'-deoxyerythrosyl-3'-sulfate anion was revealed by the authors on the basis of chemical and physicochemical evidences including the X-ray crystallographic analysis. In this study, three analogs (2,3,4)lacking hydroxyl and/or hydroxymethyl groups of the side chain of 1 and O-Desulfonated salacinol (5)were synthesized, and their inhibitory activities against α-glucosidase examined.Compounds 2,3,4 were synthesized by applying the ring-opening method of the cyclic sulfate with 1,4-dideoxy-1,4-epithio-D-arabinitol (6a). The cyclic sulfates, 1,3-propanediol 1,3-cyclic sulfate (7),2-O-benzylglycerol 1,3-cyclic sulfate (8)and 4-O-tert-b … More utyldimethylsilyl-2-deoxy-L-erythtitol 1,3-cyclic sulfate (9),used for the side chain of the analogs 2, 3, 4, were derived from 1,3-propanediol, glycerin and D-glucose in good yield, respectively. Coupling reaction of 7 with 6a gave the desired 2 in 61% yield. Deprotection of coupled products obtained from 7 and 8 in a manner similar to that used for 6a gave 3 and 4 in good yield. On the other hand, acidic methanolysis of 1 gave 5 in quantitatively yield. The α-glucosidase inhibitory activities of them were examined for the intestinal α-glucosidase in vitro. Three simpler analogs (2,3,4) showed less inhibitory activity compared to 1, and proved the importance of cooperative role of the polar substituents to exhibit the α-glucosidase inhibitory activity. On the other hand, O-desulfonated analogue 5 showed a potent α-glucosidase inhibitory activity equal to that of 1, and the sulfate anion moiety of 1 was found to be not essential for the inhibitory activity. Compound 5 was also alternatively synthesized by the use of coupling reaction of epoxide, (2R,3S)-1,2-epoxy- 3,4-bis(benzyloxy)butane (10), easily obtaine from D-isoascorbic acid, with O-benzylated thiosugar 6b. Hydrogenolysis of the coupled product gave 5 in good yield. Less