NOVEL GLYCOSIDASE INHIBITORS AS ANTICANCER AGENTS

作为抗癌剂的新型糖苷酶抑制剂

• 批准号: 6173232
• 负责人: William H. Pearson
• 金额: $ 24.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-08 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173232
• 关键词: active sites; affinity chromatography; analog; antineoplastics; biochemistry; chemical structure; drug adverse effect; drug design /synthesis /production; enzyme inhibitors; glycosidases; indolizines; lysosomes; mannosidase; neoplastic cell; pharmacokinetics; protein purification

Polyhydroxylated alkaloids (azasugars) have been the subject of intense study due to their glycosidase inhibitory activity and their potential as therapeutic agents. Glycosidases play a vital role in the biosynthesis and processing of the oligosaccharide chains of glycoproteins, molecules that are widely expressed on cell surfaces and are involved in a number of important biological functions and recognition events. The indolizidine swainsonine (SW), for example, is an alpha-mannosidase inhibitor that exhibits encouraging anticancer activity including immune stimulation and the inhibition of tumor growth. The anticancer activity of SW is attributed to its ability to inhibit the formation of certain "complex-type" cell surface glycoproteins which are found in abundance on tumor cells. SW is currently being studied in clinical trials as an anticancer agent. Based on in vitro and in vivo testing, SW has been found to reduce tumor cell adhesion to the vascular endothelium, inhibit tumor cell invasion through the extracellular matrix, stimulate immune activity against tumor cells, provide protection of the host against the immunosuppressive proteins produced by tumor cells and provide protection of the host against the lethality of several traditional cytotoxic chemotherapeutic agents. Unfortunately, two significant problems stand in the way of the development of this drug. First, it is very difficult to obtain from either natural or synthetic sources. Second, SW causes an undesired inhibition of lysosomal alpha- mannosidases, which induces a reversible phenocopy of the genetic lysosomal storage disease alpha-mannosidosis. This inhibition is also believed to be responsible for other side-effects. The initial results of these trials, while promising, indicate the need for second generation drugs with improved selectivity for the Golgi processing mannosidases and not the lysosomal catabolic mannosidases. Furthermore, these second-generation drugs should be available in large quantities. The overarching goal of the proposed work is to synthesize, in useful quantities, mannosidase-inhibitory analogs of swainsonine with improved prospects for use as anticancer drugs. A secondary goal is to design and synthesize compounds which will help understand the mechanism of the selective inhibition of certain glycoprotein processing enzymes, and to provide compounds of use as biochemical tools (e.g., affinity matrices).

多羟基生物碱(氮杂糖)由于其糖苷酶抑制活性和作为治疗药物的潜力，一直是研究的热点。糖苷酶在糖蛋白的寡糖链的生物合成和加工中起着至关重要的作用，糖蛋白是广泛表达在细胞表面的分子，参与了许多重要的生物学功能和识别事件。例如，吲哚利定苦马豆素(Sw)是一种α-甘露糖苷酶抑制剂，表现出令人鼓舞的抗癌活性，包括免疫刺激和抑制肿瘤生长。其抗癌活性归因于其抑制某些“复合型”细胞表面糖蛋白的形成，这种糖蛋白在肿瘤细胞中大量存在。目前，作为一种抗癌剂，SW正在进行临床试验。体外和体内实验表明，SW可以减少肿瘤细胞与血管内皮细胞的黏附，通过细胞外基质抑制肿瘤细胞的侵袭，刺激针对肿瘤细胞的免疫活性，保护宿主免受肿瘤细胞产生的免疫抑制蛋白的影响，并保护宿主免受几种传统细胞毒性化疗药物的伤害。不幸的是，有两个重大问题阻碍了这种药物的开发。首先，无论是从天然来源还是从合成来源获得它都非常困难。其次，SW引起溶酶体α-甘露糖苷酶的不良抑制，从而导致遗传性溶酶体储存疾病α-甘露糖苷症的可逆表型。这种抑制也被认为是其他副作用的原因。这些试验的初步结果虽然很有希望，但表明需要对高尔基体处理甘露糖苷酶而不是溶酶体分解代谢甘露糖苷酶的第二代药物具有更好的选择性。此外，这些第二代药物应该大量供应。这项拟议工作的总体目标是大量合成甘露糖苷酶抑制类似物苦马豆素，并改善其用作抗癌药物的前景。第二个目标是设计和合成有助于了解某些糖蛋白加工酶选择性抑制的机制的化合物，并提供用作生化工具的化合物(例如，亲和基质)。