SOLID-PHASE METHODS FOR THE PREPARATION OF GLYCOPEPTIDES

糖肽的固相制备方法

• 批准号: 3438614
• 负责人: LARRY S TRZUPEK
• 金额: $ 5.66万
• 依托单位: FURMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-05-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3438614
• 关键词: aminoacid; chemical cleavage; chemical structure function; chemical synthesis; dipeptides; esters; glycopeptides; glycosides; high performance liquid chromatography; infrared spectrometry; nuclear magnetic resonance spectroscopy; oxidation; polymers; sulfones

A convenient route for the preparation of model glycopeptides would be of enormous importance in developing an understanding of the chemical, biochemical, and biophysical properties of these materials. Solution-phase syntheses of some glycopeptides have been reported, but less work has been carried out on the use of solid-phase methods in this field, largely due to the chemical sensitivity of the glycosidic linkage. One possible approach to this problem is the use of the Kaiser-DeGrado procedure for solid- phase synthesis - this method involves the removal of a peptide chain from solid support under exceedingly mild conditions, using an amino acid ester as the cleaving agent. Investigation of the utility of this procedure in the synthesis of glycopeptides will involve two major approaches - the use of glycosylated amino acids as the cleaving agents, thus generating C-terminal glycopeptides, and the use of activatable aryl esters of amino acids as cleaving agents, thus providing a route to potential peptide active esters. Both of these approaches have the advantage of introducing a sensitive group in the final, mild step of the method, and a combination of these two strategies would provide a general route to glycopeptides. The study of the preparation of C-terminal glycopeptides will initially involve the preparation of a series of simple glycodipeptides, generated by the reaction of the acetate salt of a glycosylated serine derivative with various N-protected amino acids attached via oxime ester linkages to a polymer support. Structural features essential to the success of this process will be evaluated in this way. Later studies will extend to the preparation of increasingly larger glycopeptides, and practical points such as the ease of deprotection of these materials will be addressed. The reactions will be followed by IR and HPLC, and isolated product glycopeptides will be characterized by high-field NMR. A similar strategy (beginning first with simple dipeptides) will be developed for the study of the preparation of methylthiophenyl esters of peptides. Likely side-reactions which could complicate the solid-phase synthesis of these esters will be quantitatively investigated. The oxidation of the resulting esters to their electrophilic sulfone analogs will be carried out, and the use of these in fragment coupling processes will be evaluated.

一种简便的糖肽模型制备方法 对我们理解 化学，生物化学，和生物物理特性， 材料. 一些糖肽的液相合成具有 但在使用 固相方法在这一领域，主要是由于化学 糖苷键的敏感性。 的一种可能的方法 这个问题是使用Kaiser-DeGrado程序进行固体- 相合成-这种方法涉及去除肽 链从固体支持物在非常温和的条件下，使用 氨基酸酯作为裂解剂。 调查 该方法在糖肽合成中的应用将 涉及两种主要方法-使用糖基化氨基 酸作为裂解剂，从而产生C-末端 糖肽和氨基的可活化芳基酯的用途 酸作为裂解剂，从而提供了一种潜在的途径， 肽活性酯。 这两种方法都具有 在最后的温和步骤中引入敏感基团的优点 这两种策略的结合将 提供了糖肽的一般途径。 C-末端糖肽制备的研究将为糖肽的制备提供新的途径 最初涉及一系列简单的 糖二肽，由糖基化的糖基化的糖基化合物的乙酸盐 具有各种N-保护氨基的糖基化丝氨酸衍生物 酸通过肟酯键连接到聚合物载体上。 对这一进程的成功至关重要的结构特征将是 以这种方式评价。 以后的研究将扩展到 制备越来越大的糖肽， 诸如这些材料的脱保护的容易性的要点将是 处理。 将通过IR和HPLC跟踪反应，并且 分离的产物糖肽的特征在于高场 匪r 一个类似的策略（首先从简单的二肽开始）将是 用于甲硫基苯的制备研究 肽的酯。 可能的副反应， 这些酯固相合成将定量地 研究了 将所得酯氧化成它们的 将进行亲电砜类似物的制备， 将评价这些在片段偶联过程中的作用。