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SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

C-二糖的合成和生物学评价

基本信息

批准号：
2391377
负责人：
OLIVIER R MARTIN
金额：
$ 10.99万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-07-01 至 1998-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2391377
关键词：
O glycosidase analog beta glucosidases carbohydrate metabolism chemical structure function chemical synthesis disaccharides enzyme inhibitors glycosides hydrolysis membrane activity methylene chloride oligosaccharides

项目摘要

The principal objectives of this program are the synthesis of analogs of disaccharides in which the interglycosidic oxygen atom is replaced by a methylene group, and the evaluation of their activity as glycosidase inhibitors. The scope of the program will be extended, during the next budget period, to a new class of pseudodisaccharides, namely aza-C- disaccharides, in which the ring oxygen atom of the "non-reducing" unit is replaced by an imino (-NH-) group (equivalent to elusive nojirimycin- disaccharides). The specific aims for the next budget period are (1) the preparation of specific branched C-disaccharides (e.g., C-lactosamine), (2) the development of efficient synthetic approaches to aza-C-disaccharides (e.g., aza-C-maltose), and (3) the preparation first examples of pseudotrisaccharides (C,O and O,C-trisaccharides). As chemically inert and structurally extremely similar analogs of the natural substrates of several types of glycosidase, the proposed pseudeooligosaccharides are likely to behave as potent, strictly competitive inhibitors of the hydrolytic process catalyzed by these enzymes. Maltose analogs, in particular, are especially significant targets as potential modulators of carbohydrate metabolism: as highly selective inhibitors of the alpha-glucosidases of the digestive tract, these compounds might provide a means of controlling the intestinal glucose uptake and thus prove useful in the treatment of metabolic diseases such as diabetes mellitus. Furthermore, as potential inhibitors of the "trimming" glycosidase involved in the processing of the oligosaccharide chains of glycoproteins (such as for example of the envelope glycoprotein of the human HIV virus), the proposed pseudodisaccharides (e.g., aza-C- kojibiose) might also posses significant antiviral activities. A major challenge in synthetic carbohydrate chemistry, the synthesis of C-disaccharides require the coupling of two sugar units by a C-C bond forming reaction. Efficient methodologies based on polar (mitroaldol) and radical (SRN1) processes have been developed and have provided expeditious syntheses of linear" C-disaccharides. "Branched" C- disaccharides will be prepared by way of SRN1-coupling processes and aza- C-disaccharides by way of radical or polar coupling processes. The biological activity of the pseudooligosaccharides will be determined in our laboratory using simple glycosidase, and in specialized laboratories using alpha and Beta-glucanases (in collaboration with Dr. H. Driguez, CNRS-Grenoble, and Dr. M. Claeyssens, University of Gent, respectively).

该计划的主要目标是合成的类似物，其中糖苷间氧原子被取代的二糖亚甲基，并评价它们作为糖苷酶的活性抑制剂的该计划的范围将扩大，在未来预算期间，一类新的假二糖，即氮杂-C- 二糖，其中“非还原”单元的环氧原子被亚氨基（-NH-）基团取代（相当于难以捉摸的野尻霉素- 二糖）。下一个预算期的具体目标是：（1）编制特定的支链C-二糖（例如，C-乳糖胺），（2）氮杂-C-二糖的有效合成方法的开发 (e.g.,氮杂-C-麦芽糖），和（3）制备第一实施例假三嗪（C，O和O，C-triphosphate）。作为化学惰性和结构极其相似的类似物，提出了几种类型的糖苷酶的天然底物，假低聚糖可能表现为有效的，严格地说，这些催化的水解过程的竞争性抑制剂内切酶特别是麦芽糖类似物，作为碳水化合物代谢的潜在调节剂的靶点：消化道α-葡糖苷酶的选择性抑制剂，这些化合物可能提供一种控制肠道葡萄糖摄入，因此证明可用于治疗代谢性疾病糖尿病等疾病。此外，作为潜在的抑制剂，的“修剪”糖苷酶参与的加工，糖蛋白的寡糖链（例如，人HIV病毒的包膜糖蛋白），假二糖（例如，氮杂-C-曲二糖）也可能显著的抗病毒活性。合成碳水化合物化学中的一个主要挑战是， C-二糖需要两个糖单元通过C-C键偶联形成反应。基于极性（mitroaldol）的高效方法和自由基（SRN 1）工艺已经开发并提供了线性”C-二糖“的快速合成。 “分支”C 二糖将通过SRN 1-偶联方法和氮杂- C-二糖通过自由基或极性偶联过程。将测定假寡糖的生物活性在我们的实验室中使用简单的糖苷酶，实验室使用α和β-葡聚糖酶（与Dr. H. Driguez、CNRS-Grenoble和M. Claeyssens，根特大学，分别）。