Synthesis and Development of Useful Glycosidase Inhibitors.

近年来，由于人们对糖类在生物过程中的重要作用的认识日益加深，糖苷酶抑制剂的合成和开发受到了越来越多的关注。因此，对糖苷酶抑制剂的化学和生化研究可能有助于了解糖尿病、癌症和艾滋病等难治性疾病的分子基础，也可能为我们提供治疗方法。作为正在进行的阐明糖苷酶抑制剂作用模式的计划的一部分，我们合成了环磷脂醇、NAGSTATIN和瓜拉霉素及其类似物，它们具有不同的构型和功能。NAGSTATIN是N-乙酰-β-D-氨基葡萄糖苷酶的天然抑制剂，愈创木素是一种抗药物替代品。从糖类化合物出发，通过咪唑和三氮唑类化合物的分子间和分子内亲核反应，合成了包括各种羟基和三氮唑类似物的Nagstatin。它们的糖苷酶抑制活性是底物特异性的，这表明糖苷酶特别识别糖苷酶抑制剂的每个碳和构型，因此，这些抑制剂是相应的糖苷的拮抗剂。瓜拉霉素的抗螨活性可能是由于其麦芽糖酶抑制活性所致。

In recent years, much attention has focused on the synthesis and development of glycosidase inhibitors because of an increasing awareness of the vital role playd by carbohydrates in biological processes. Therefore, the chemical and biochemical studies on glycosidase inhibitors may lead to understand the molecular basis of intractable diseases such as diabetes mellitus, cancer and AIDS,and may also provide us therapeutic approaches to them.As part of an ongoing program to clarify the mode of action of glycosidase inhibitors, we have synthesized cyclophellitol, nagstatin and gualamycin, and their analogs having different configurations and functionalities.Nagstatin is a natural inhibitor of N-acetyl-beta-D-glucosaminidase, and gualamycin is an antimite substance.Herein, nagstatins including a variety of hydroxyl and triazole analogs have been synthesized from carbohydrates by inter-and intramolecular nucleophilic reaction of the imidazole and triazole moieties. Their glycosidase inhibiting activities were quite substrate-specific, indicating that the glycosidases recognize especially each carbons and configurations of the glycosidase inhibitors, and consequently, the inhibitors serve as antagonists of the corresponding glycopyranosides.Total synthesis of gualamycin has been accomplished from three kinds of carbohydrates through glycosylation of a thio-phenol derivative of the disaccharide portion with a pyrrolidine-aglycone. The anti-mite activity of gualamycin was suggested to be due to its maltase inhibiting activity.