NOVEL GLYCOSIDASE INHIBITORS AS ANTICANCER AGENTS

多羟基化生物碱（azasugars）由于其糖苷酶抑制活性和作为治疗剂的潜力而成为研究热点。 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，糖蛋白是在细胞表面广泛表达的分子，并参与许多重要的生物学功能和识别事件。例如，吲哚里西啶苦马豆素（SW）是一种α-甘露糖苷酶抑制剂，其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。SW的抗癌活性归因于其抑制某些“复合型”细胞表面糖蛋白形成的能力，这些糖蛋白在肿瘤细胞上大量存在。SW目前正在作为抗癌药物进行临床试验研究。基于体外和体内试验，已发现SW可减少肿瘤细胞与血管内皮的粘附，抑制肿瘤细胞通过细胞外基质的侵袭，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剂的致死性影响。不幸的是，两个重要的问题阻碍了这种药物的发展。首先，它很难从天然或合成来源获得。其次，SW引起溶酶体α-甘露糖苷酶的不期望的抑制，其诱导遗传性溶酶体贮积病α-甘露糖苷沉积症的可逆表型。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有希望，但表明需要对高尔基体加工甘露聚糖酶而不是溶酶体分解代谢甘露聚糖酶具有改进的选择性的第二代药物。此外，这些第二代药物应大量供应。所提出的工作的总体目标是合成，在有用的数量，苦马豆素的甘露糖苷酶抑制类似物作为抗癌药物使用的前景改善。第二个目标是设计和合成有助于理解选择性抑制某些糖蛋白加工酶的机制的化合物，并提供用作生物化学工具的化合物（例如，亲和矩阵）。

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).