NOVEL GLYCOSIDASE INHIBITORS AS ANTICANCER AGENTS

多羟基生物碱（氮糖）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。糖苷酶在糖蛋白低聚糖链的生物合成和加工中起着至关重要的作用，糖蛋白分子在细胞表面广泛表达，并参与许多重要的生物学功能和识别事件。例如，吲哚嗪swainsonine （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，包括免疫刺激和肿瘤生长抑制。SW的抗癌活性是由于它能够抑制肿瘤细胞上大量存在的某些“复杂型”细胞表面糖蛋白的形成。目前，SW作为抗癌药物正在临床试验中进行研究。在体外和体内试验的基础上，研究人员发现，SW可以降低肿瘤细胞对血管内皮的粘附，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侵害，并保护宿主免受几种传统细胞毒性化疗药物的杀伤。不幸的是，有两个重大问题阻碍了这种药物的开发。首先，无论是天然的还是合成的来源都很难获得。其次，SW引起溶酶体α -甘露糖苷酶的抑制，从而诱发遗传性溶酶体储存病α -甘露糖苷病的可逆表型。这种抑制作用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加工甘露糖糖酶而不是溶酶体分解代谢甘露糖糖酶具有更高选择性的第二代药物。此外，这些第二代药物应该大量可用。提出的工作的总体目标是合成，在有用的数量，甘露糖苷酶抑制类似物的马豆素与改善前景使用作为抗癌药物。第二个目标是设计和合成化合物，这将有助于理解某些糖蛋白加工酶的选择性抑制机制，并提供用作生化工具的化合物（例如，亲和基质）。

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).