SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

开发了一种合成“C-二糖”的方法， 具有亚甲基（CH 2）的未知类假二糖 而不是在糖苷间键上的氧原子，并且 其生物学特性的研究是主要目标 的拟议研究。 由于他们完全不尊重 这些假二糖非常有趣 天然二糖的类似物，预期其作为有效的 糖基水解酶的竞争性抑制剂。 如图所示， 碳水化合物衍生物，包括S-二糖、糖苷酶抑制剂 不仅是有用的生化工具， 在治疗和研究中的应用，在生理 代谢性疾病，如溶虫贮积病， 糖尿病;例如阿卡波糖，一种含假糖的寡糖， 已知可改善胰岛素依赖型糖尿病患者的代谢状况。 综合方法论在关键步骤中涉及到刘易斯 由C-糖基衍生的甲硅烷基硝基膦酸酯的酸催化缩合 硝基甲烷（对于非还原性假二糖）或来自C-硝基甲基 具有糖基的碳水化合物衍生物（用于还原假二糖） 乙酸酯（对于β-假端基异构体）或糖基氟化物（对于α-端基异构体）， 然后进行自由基反硝化和脱保护， 中间体的 海藻糖C-类似物（α，α 以及β，β）纤维二糖、麦芽糖、乳糖和蔗糖。 为 制备1，6-连接的假二糖（葡萄糖和/或半乳糖 单元），关键的偶联反应将通过硝基醛醇实现 C-糖基硝基甲烷的甲硅烷基硝基膦酸酯与 二醛糖 将进行结构分析，重点是 不存在外异头效应，以及初步的生物化学 研究：假二糖对 相应的O-二糖的酶促水解将是 测定

The development of a methodology for the synthesis of "C-disaccharides", a yet unknown class of pseudodisaccharides having a methylene group (CH2) instead of an oxygen atom at the interglycosidic linkage, and the investigation of their biological properties are the principal objectives of the proposed research. Owing to their complete inertness with respect to hydrolysis, these pseudodisaccharides are extremely interesting analogues of the natural disaccharides that are expected to act as potent competitive inhibitors of glycosyl hydrolases. As shown with other carbohydrate derivatives including S-disaccharides, glycosidase inhibitors are not only useful biochemical tools, but have found also important applications in the treatment and the study, under physiological conditions, of metabolic diseases such as the lysozomal storage disease and diabetes; for example, acarbose, a pseudosugar-containing oligosaccharide, is known to improve the metabolic condition of insulin-dependent diabetics. The synthetic methodology involves, in the key steps, the Lewis acid-catalyzed condensation of a silyl nitronate derived from a C-glycosyl nitromethane (for non-reducing pseudodisaccharides) or from a C-nitromethyl carbohydrate derivative (for reducing pseudodisaccharides) with a glycosyl acetate for beta-pseudoanomers) or a glycosyl fluoride (for alpha-anomers), followed by radical denitration and deprotection of the resulting intermediates. The synthesis of the C-analogues of trehalose (alpha,alpha and beta,beta) cellobiose, maltose, lactose, and sucrose is planned. For the preparation of 1,6-linked pseudodisaccharides (gluco and/or galacto units), the key coupling reaction will be achieved by nitroaldol condensation of the silyl nitronate of C-glycosyl nitromethanes with dialdosugars. Structural analysis will be performed, with emphasis on the absence of exo-anomeric effect, as well as preliminary biochemical investigations: the inhibitory effect of the pseudodisaccharides on the enzymatic hydrolysis of the corresponding O-disaccharides will be determined.