INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

细胞表面碳水化合物在许多重要的生物中起着关键作用。 细胞-细胞识别、细胞-细胞黏附、细胞-基质等现象 黏附、淋巴细胞贩运和通货膨胀。了解酶 它处理复杂碳水化合物中的重要糖苷键， 糖蛋白和糖脂已成为糖化学的中心目标 在基础研究和医学方面。基于这些靶点的药物也将 用于治疗糖尿病、转移性癌症和溶酶体储存 疾病；有些可能表现出强大的抗病毒和抗肿瘤特性，如 井。这项更新提案概述了研究的四个具体目标。 (L)NAGSTATIN等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“糖仿制”(例如，特定的 葡萄糖苷酶II的抑制剂)可能对阐明 钙粘蛋白(一种伴侣蛋白)在蛋白质折叠中。几个新的杂环 糖苷酶抑制剂被设计成在构象上类似于 糖苷水解的平坦过渡态。 (2)半乳鞘糖脂与另一种途径有关 用于在CD4阴性细胞中感染HIV-1。通过使用半乳糖神经酰胺 类似物将糖脂结合到天然的HIV外壳蛋白gpl20和 它的片段，未来的抗病毒治疗的新策略将是 发展起来的。在相关工作中，葡萄糖神经酰胺合成酶的抑制剂将 被合成以阐明鞘磷脂在癌症中的代谢作用 恶性肿瘤、肿瘤生长和转移。 (3)几个新的核糖核苷和阿拉伯核苷类似物将是 用氨基取代戊糖环合成的酰胺类化合物， 导致了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)， 在人工合成核苷的数据库搜索中都没有找到这两种化合物 在美国国立卫生研究院进行了生物活性评估。然而，它们显然是 被核苷加工酶如核苷水解酶识别，以及 将针对核苷激酶、DNA聚合酶和反向 转录酶。 (4)合成碳环糖苷酶抑制剂的努力，如 海藻糖酶抑制剂三唑林将专注于立体选择性的新路线 对假性扁桃体和假性氨基扁桃体，对糖蛋白和 糖脂类似物，这些新的糖模拟物。

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.