INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

细胞表面碳水化合物在许多重要的生物学过程中起着关键作用。 现象，例如细胞-细胞识别、细胞-细胞粘附、细胞-基质 粘附、淋巴细胞运输和膨胀。了解酶 其处理复杂碳水化合物中的重要糖苷键， 糖蛋白和糖脂已经成为糖化学的中心目标 在基础研究和医学上。基于这些靶点的药物也将被 可用于治疗糖尿病、转移性癌症和溶酶体贮积症 疾病;有些可能显示出有效的抗病毒和抗肿瘤特性， 好.这项更新建议概述了四个具体的研究目标。 (l)那他汀（及其它N-乙酰-D-氨基葡萄糖苷酶）的合成 抑制剂）可以导致新的避孕药，并限制肿瘤细胞 转移其他杂环“糖模拟物”（例如，特异性糖模拟物） 葡萄糖苷酶II抑制剂）可能在阐明 钙连接蛋白（一种伴侣蛋白）在蛋白质折叠中的作用。几种新杂环 糖苷酶抑制剂已经被设计成在构象上类似于 糖苷水解的平坦过渡态。 (2)半乳糖鞘脂参与了一种替代途径， HIV-1感染的CD 4阴性细胞。通过使用半乳糖神经酰胺 类似物以映射糖脂与天然HIV外壳蛋白gp 120的结合， 它的片段，抗病毒治疗的前瞻性新策略， 开发在相关的工作中，葡糖神经酰胺合酶的抑制剂将 来阐明鞘脂在癌症中的代谢作用 恶性肿瘤、肿瘤生长和转移。 (3)几个新的核糖和阿拉伯糖核苷类似物的家庭将是 通过用酰胺腙、酰胺肟和 胍，导致前所未有的化学实体。这些实体 含有两个不常见的结构元素（C=N，芳基肼基键）， 在合成核苷的数据库搜索中， 在NIH进行生物活性评估。然而，他们显然 被核苷加工酶如核苷水解酶识别，和 将针对核苷激酶、DNA聚合酶和逆转录酶进行筛选 转录酶。 (4)合成碳环糖苷酶抑制剂的努力，如 海藻糖酶抑制剂trehazolin，将集中在一个立体选择性的新途径 假戊糖和假氨基戊糖，以及糖蛋白， 这些新型糖模拟物的糖脂类似物。

Cell-surface carbohydrates play key roles in many important biological phenomena, e.g. cell-cell recognition, cell-cell adhesion, cell-matrix adhesion, lymphocyte trafficking, and inflation. Understanding the enzymes which process important glycosidic bonds in complex carbohydrates, glycoproteins, and glycolipids has become a central goal of glycochemistry in basic research and medicine. Drugs based on these targets will also be useful in treating diabetes, metastatic cancer and lysosomal storage diseases; some may display potent antiviral and antitumor properties as well. This renewal proposal outlines four specific objectives for study. (l) The synthesis of nagstatin (and other N-acetyl-D-glucosaminidase inhibitors) can lead to new contraceptives, and limit tumor cell metastasis. Other heterocyclic "glycomimetics" (for example, specific inhibitors of glucosidase II) could be of value in elucidating the role of calnexin (a chaperonin) in protein folding. Several new heterocyclic glycosidase inhibitors have been designed to resemble the conformationally flattened transition state of glucoside hydrolysis. (2) Galactosphingolipids have been implicated in an alternative pathway for HIV-1 infection in CD4-negative cells. By using galactosylceramide analogs to map glycolipid binding to the native HIV coat protein gpl20 and its fragments, prospective new strategies for antiviral therapy will be developed. In related work, inhibitors of glucosylceramide synthase will be synthesized to elucidate the metabolic roles of sphingolipids in cancer malignancy, tumor growth and metastasis. (3) Several new families of ribo- and arabino-nucleoside analogs will be synthesized by replacing the pentose ring with amidrazones, amidoximes and guanidines, leading to unprecedented chemical entities. These entities contain two uncommon structural elements (C=N, arylhydrazino linkage), neither of which is found in database searches of synthetic nucleosides evaluated at NIH for biological activity. However, they are clearly recognized by nucleoside processing enzymes like nucleoside hydrolase, and will be screened against nucleoside kinases, DNA polymerases, and reverse transcriptases. (4) Efforts to synthesize carbocyclic glycosidase inhibitors, like the trehalase inhibitor trehazolin, will focus on a stereoselective new route to pseudopentoses and pseudo-aminopentoses, and on glycoprotein and glycolipid analogs of these novel glycomimetics.