SYNTHESIS OF ANTIBIOTICS

抗生素的合成

• 批准号: 3126918
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 33.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-03-01 至 1994-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3126918
• 关键词: AIDS; antibiotics; antibody formation; antineoplastics; antiviral agents; aromatase; castanospermine; chemical synthesis; cyclosporines; doxorubicin; drug design /synthesis /production; high performance liquid chromatography; nucleosides; oligosaccharides; stereochemistry

The long-term objectives of this project involve the development of new synthetic strategies and the application of these strategies to the synthesis of complex systems of biological interest. In the AI program we hope to apply these capabilities to the synthesis of substances of interest as potential antibiotics, antiviral agents, or as antitumor drugs. In this next grant period we will focus on a broad range of chemical goals with diverse biological implications. A major and comprehensive effort is envisioned in the synthesis of oligosaccharides. We will study a potential menu of reactions whereby glycals will be substrates for electrophilically induced glycosidation. Included in this work are 2- deoxy, 2-halo, 2-amino, and "normal" 2-oxygenated oligosaccharides. The ultimate goal is the development of a capability in polymer based oligosaccharide construction. Specific targets in the carbohydrate area will be novel glycosides of avermectin and adriamycin, as well as the full carbohydrate portion of allosamidin. A study of the use of these concepts for the synthesis of novel nucleosides of interest in anti-AIDS therapy will be launched. Some new strategies in the synthesis of heterocycles have been developed. The application of these findings to the total synthesis of several key target systems will be pursued. Particularly interesting in this regard are castanospermine and FR900482. Castanospermine has been shown to have some anti-AIDS potential as an inhibitor of enzymes responsible for glycoprotein maturation. FR900482 has engendered considerable interest due to its very novel structure and reported "exceptionally potent" antitumor activity. We also will be directing a great deal of effort to the synthesis of esperamicin. Here the challenge goes beyond the complexity of the synthetic problem. Through suitable structures, which can be obtained uniquely through synthesis, a better understanding of the mode of action of this important antitumor agent will be achieved. A major effort will be directed toward the total synthesis of FK-506. This compound is the most powerful immunosuppressant now known (100 more active than cyclosporine). We will also continue our quinone- hydroquinone chemistry in the context of the biomimetic chemistry of adriamycin. Through these studies a superior insight into the mode of action of the antaracyclines will be sought. The completion of our efforts in the tunicamycin area is envisioned. At the present time the only remaining problem is the construction of the trehalose type of linkage.

该项目的长期目标包括开发新的 综合策略及其在英语教学中的应用 具有生物学意义的复杂系统的合成。在人工智能项目中 我们希望将这些能力应用于合成 兴趣作为潜在的抗生素、抗病毒药物或抗肿瘤药物 毒品。 在下一个资助期，我们将专注于广泛的化学品 具有不同生物学意义的目标。一项重大而全面的 可以预见，低聚糖的合成需要付出努力。我们会研究 一个潜在的反应菜单，其中甘氨酸将成为底物 亲电诱导的糖苷化。这项工作包括2- 脱氧，2-卤代，2-氨基，和“正常”的2-含氧寡糖。这个 最终目标是发展以聚合物为基础的能力 低聚糖结构。碳水化合物领域的具体目标 将是阿维菌素和阿霉素的新型糖苷，以及 别三聚氰胺的完整碳水化合物部分。关于这些词的用法的研究 抗艾滋病新核苷的合成概念 治疗将会启动。 在杂环化合物的合成中，一些新的策略已经被开发出来。 这些发现在几个关键字的全合成中的应用 将推行目标系统。在这方面特别有趣 分别是蓖麻籽胺和FR900482。蓖麻花已被证明具有 一些潜在的抗艾滋病酶起到了抑制作用 糖蛋白成熟。FR900482引起了相当大的兴趣 由于它非常新颖的结构，并被报道为“异常有效” 抗肿瘤活性。 我们还将投入大量精力来合成 埃司帕米星。这里的挑战超越了复杂的 合成问题。通过合适的结构，可以获得 独特的通过综合，更好地理解行动模式 这一重要的抗肿瘤药物将会实现。 一个主要的努力将指向FK-506的全合成。 这种化合物是目前已知的最有效的免疫抑制剂(100多种 比环孢素有活性)。我们还将继续我们的苯二酚- 对苯二酚化学在仿生化学中的应用 阿霉素。通过这些研究，更好地洞察了 将寻求抗马拉环类药物的作用。完成我们的 在衣霉素领域的努力是设想的。在这个时候， 唯一剩下的问题是海藻糖型的结构 联动。