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

Salacinol(1)是从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的一种有效的α-葡萄糖苷酶抑制剂，在斯里兰卡和印度传统上用于治疗糖尿病。基于x射线晶体分析等理化证据，揭示了其内盐由1-脱氧-4-硫代阿拉伯糖呋喃基阳离子和1'-脱氧红基-3'-硫酸盐阴离子组成的独特螺状结构。本研究合成了3个类似物（2,3,4），它们缺乏1和o -脱硫salacinol(5)侧链上的羟基和/或羟甲基，并检测了它们对α-葡萄糖苷酶的抑制活性。采用环硫酸酯与1,4-二脱氧-1,4-上皮-d -阿拉伯糖醇（6a）开环法合成化合物2,3,4。以1,3-丙二醇、甘油和d -葡萄糖为原料，分别制备了1,3-丙二醇1,3-环硫酸酯(7)、2- o -苄基甘油1,3-环硫酸酯(8)和4- o -叔丁基硫酸酯(9)，用于类似物2,3,4的侧链。7与6a偶联反应得到所需的2，产率为61%。从7和8中得到的偶联产物以类似于6a的方式去保护，使3和4获得良好的产量。另一方面，1的酸性甲醇分解量产率为5。体外测定其对肠道α-葡萄糖苷酶的抑制活性。3个较简单的类似物（2、3、4）表现出较低的α-葡萄糖苷酶抑制活性，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 -脱硫类似物5表现出与1相当的α-葡萄糖苷酶抑制活性，并且发现1的硫酸盐阴离子部分不是抑制活性所必需的。化合物5也可由易于从d -异抗坏血酸中得到的环氧化合物(2R,3S)-1,2-环氧- 3,4-双（苯氧基）丁烷（10）与o -苄基化硫代糖6b偶联合成。偶联产物氢解得到5，产率高。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