Total Synthesis of the Adjuvant Saponin Jujuboside A

佐剂皂苷大枣苷A的全合成

• 批准号: 8000290
• 负责人: Bryan James Cowen
• 金额: $ 4.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2012-07-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000290
• 关键词: Adjuvant; Adjuvanticity; Alkenes; Antigens; Area; Biological Factors; Biomimetics; Cations; Chemicals; Communicable Diseases; Cyclization; Development; Exhibits; Goals; Immunotherapy; Malignant Neoplasms; Methodology; Methods; Molecular; Organic Synthesis; Preclinical Testing; Preparation; Public Health; Reaction; Reagent; Research; Research Design; Route; Sampling; Saponin; Saponins; Source; Sulfoxide; System; Techniques; Time; chemical synthesis; cost; glycosylation; interest; novel; preclinical study; public health relevance; vaccine development

DESCRIPTION (provided by applicant): Chemical synthesis of molecular immunostimulating adjuvants is an important, underdeveloped area in vaccine development. Saponin natural products have shown promising adjuvant activity when co-administered with subunit antigen constructs. However, methods for their isolation from natural sources are often tedious and wasteful. Therefore, synthetic access to such entities for preclinical study should further the fields of cancer and infectious disease immunotherapy. Jujuboside A, a saponin natural product, is a promising candidate for study as it has been found to exhibit higher adjuvanticity and lower hemolytic activity as compared with the established adjuvant known as QS-21A. This project will study the total chemical synthesis of this novel saponin. Objectives: The goal of this project is to establish a synthetic route to jujuboside A providing pure samples of the natural product for preclinical testing as a molecular adjuvant. Specific Aims: (1) Synthesis of the pentasaccharide fragment of jujuboside A through application of a catalytic sulfoxide-promoted glycosylation strategy. (2) Synthesis of the structurally unique aglycone fragment of jujuboside A. This will involve development of a cation-olefin cyclization reaction and a C-H insertion reaction as the key synthetic steps. Study design: This project will utilize techniques of organic synthesis to construct the target of interest, jujuboside A. A convergent synthetic strategy will focus on efficient preparation of a pentasaccharide fragment and an aglycone fragment. Concerning the former, a novel catalytic sulfoxide-promoted methodology for glycosidic bond formations will be applied. This method benefits from the use of substoichiometric quantities of certain chemical reagents and convenient reaction conditions. Both these factors should limit the required cost and time associated with pentasaccharide preparation. The synthesis of the aglycone will be undertaken employing a biomimetic olefin-cation cyclization reaction. This highly simplifying transformation will prepare, in a stereocontrolled fashion, an advanced intermediate en route to jujuboside A. Additionally, a C-H insertion reaction will complete the intricate carbocyclic ring system of jujuboside A. PUBLIC HEALTH RELEVANCE: This project will study the chemical synthesis of the natural product, jujuboside A. The goal of this research will be to provide sufficient quantities of this compound to enable its study for cancer and infectious disease vaccine development.

描述（由申请人提供）：分子免疫刺激佐剂的化学合成是疫苗开发中一个重要但不发达的领域。当与亚单位抗原结构共同施用时，皂苷天然产物显示出有希望的佐剂活性。然而，将它们从自然来源中分离出来的方法往往既繁琐又浪费。因此，对这些实体进行临床前研究的合成途径应进一步推动癌症和传染病免疫治疗领域的发展。红枣苷A是一种皂素天然产物，是一种很有前途的研究候选者，因为与已知的佐剂hs - 21a相比，它具有更高的佐剂性和更低的溶血活性。本课题将研究这种新型皂苷的全化学合成。目的：本项目的目的是建立一种合成红枣苷a的途径，提供天然产物的纯样品作为分子佐剂进行临床前试验。具体目的：(1)应用催化亚砜促进糖基化策略合成红枣苷A的五糖片段。(2)合成结构独特的红枣苷a苷元片段，其中以阳离子-烯烃环化反应和碳氢键插入反应为关键步骤。研究设计：本项目将利用有机合成技术构建感兴趣的靶点枣苷A。聚合合成策略将侧重于高效制备五糖片段和糖苷元片段。对于前者，将应用一种新的催化亚砜促进糖苷键形成的方法。这种方法得益于使用了某些化学试剂的亚化学计量量和方便的反应条件。这两个因素都限制了五糖制备所需的成本和时间。该苷元的合成将采用仿生烯烃-阳离子环化反应进行。这一高度简化的转化将以立体控制的方式制备出一种高级中间体，同时，C-H插入反应将完成复杂的碳环体系。