DESIGN AND SYNTHESIS OF INHIBITORS FOR GLYCOENZYMES

糖酶抑制剂的设计与合成

• 批准号: 2378287
• 负责人: YOSHITAKA ICHIKAWA
• 金额: $ 16.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2378287
• 关键词: carbohydrate biosynthesis; chemical structure function; drug design /synthesis /production; enzyme inhibitors; glycosidases; glycosyltransferase; imines; monosaccharides; oligosaccharides

Compounds that inhibit oligosaccharide biosynthesis represent valuable tools for analyzing the role of complex carbohydrates in biological processes. In particular, glycosidase inhibitors such as nojirimycin have been used to dissect specific cellular events and are now being considered as potential therapeutic agents to treat a variety of metabolic and infectious diseases. The goal of the present proposal is to design, synthesize, and evaluate the biochemical and biologic effects of a new class of mechanism-based glycosidase and glycosyltransferase inhibitors. These inhibitor candidates are designed to supply the current need for inhibitors that are both highly potent and selective. The proposed inhibitors are 1-N- iminosugar derivatives, which differ from the currently available inhibitors in possessing a nitrogen atom at the anomeric position of the pyranose ring, which was designed to mimic a model of the beta-glycosidic cleavage reaction intermediate, which has a positive charge on the anomeric position, rather than on the ring oxygen of the sugar. The structure of the proposed inhibitors -- nitrogen in the anomeric position, chair conformation, and appropriate OH substituents to enhance recognition -- is expected to make them highly specific as well as potent against glycosidases. Using this new type of inhibitor with a positive charge on the anomeric position as a probe, the enzyme mechanism will also be better understood. The general synthetic scheme, starting with a readily available carbohydrate derivative, involves i) introduction of an amino functionality, ii) formation of 1-N-iminopyranose ring, and iii) stereoselective introduction of hydroxymethyl group. The 1-N-iminosugar compounds will be further conjugated to a various alkyl groups to be a better inhibitor of glycosidases or an inhibitor of glycolipid synthesis, or to a second sugar moiety to develop sequence-specific endoglycosidase inhibitors. Given the potential specificity and potency of the proposed inhibitors, these reagents are expected to contribute not only to the study of oligosaccharide-mediated cellular events as a new probe but also to the development of inhibitor-based drugs with a wide range of clinical applications.

抑制寡糖生物合成的化合物代表有价值的化合物 分析复杂碳水化合物在生物学中的作用的工具 过程。 特别是，糖苷酶抑制剂，例如Nojirimycin 被用于剖析特定的蜂窝事件，现在正在考虑 作为治疗各种代谢和的潜在治疗剂 传染病。 本提案的目的是设计，合成和评估 基于机制的新型机制的生化和生物学效应 糖苷酶和糖基转移酶抑制剂。 这些抑制剂 候选人旨在满足当前对抑制剂的需求 既有效又有选择性。 提出的抑制剂是1-n- Iminosugar衍生品，与当前可用的不同 在具有氮原子的抑制剂处 吡喃糖环，旨在模仿β-糖苷的模型 切割反应中间体，在 异构位置，而不是在糖的环氧上。 这 拟议抑制剂的结构 - 氮在异构位置， 椅子构象和适当的OH取代基来增强识别 - 预计将使它们高度具体且有效 糖苷酶。 使用这种新型的抑制剂，并带有正电荷 作为探针的异构位置，酶机制也将更好 理解。 一般的合成方案，从容易开始 可用的碳水化合物衍生物，涉及i）引入氨基 功能，ii）形成1-N-米诺吡喃糖环和III） 羟基的立体选择性引入。 1-N-iminosugar 化合物将进一步偶联到各种烷基 更好的糖苷酶抑制剂或糖脂合成的抑制剂， 或到第二个糖部分以开发序列特异性内糖苷酶 抑制剂。 考虑到所提出的抑制剂的潜在特异性和效力， 这些试剂不仅有助于研究 寡糖介导的细胞事件作为一种新探针，但也对 开发具有广泛临床的抑制剂药物 申请。