Synthesis and Development of Useful Glycosidase Inhibitors.

近年来，由于人们越来越认识到碳水化合物在生物过程中所起的重要作用，糖苷酶抑制剂的合成和开发受到了广泛关注。因此，对糖苷酶抑制剂的化学和生物化学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。作为阐明糖苷酶抑制剂作用机制的正在进行的计划的一部分，我们合成了环皮醇、那格他汀和瓜拉霉素，和具有不同构型和功能的它们的类似物。Nagstatin是N-乙酰基-β-D-氨基葡萄糖苷酶的天然抑制剂，而Gualamycin是抗真菌物质。在本文中，包括各种羟基和三唑类似物的那他汀已经通过咪唑和三唑部分的分子间和分子内亲核反应由碳水化合物合成。它们的糖苷酶抑制活性具有很强的底物特异性，表明糖苷酶特别识别糖苷酶抑制剂的每个碳和构型，因此，抑制剂作为相应的吡喃糖苷的拮抗剂。Gualamycin是由三种碳水化合物通过二糖部分的硫代苯酚衍生物与吡咯烷糖苷配基的糖基化反应完成的。瓜拉霉素的抗螨活性可能与其麦芽糖酶抑制活性有关。

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.