IMMUNOSUPPRESSANTS--SYNTHESIS OF FK-506

免疫抑制剂--FK-506的合成

• 批准号: 3300510
• 负责人: ROBERT E IRELAND
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3300510
• 关键词: carbonyl group; cyclosporines; drug adverse effect; drug design /synthesis /production; immunosuppressive; lactones; transplantation

It is proposed to investigate the immunosuppressant activity of FK-506 and its structural analogs through the development of efficient convergent syntheses and then biological testing. The initial specific aim of this work will be the synthesis of FK-5506 in order to establish synthetic strategy and methodology. The synthetic approach is designed so that, in the long range, structural modifications can be made that will produce analogs configured so as to test the structural requirements for immunosuppression. The first clinically utilized immunosuppressant, cyclosporin A, has revolutionized organ transplant therapy. A peptide, cyclosporin A and numerous analogs have been synthesized and their biological activity studied. The recently identified FK-506 is a more active immunosuppressant antibiotic with different and fewer side effects. FK-506 is, in contrast to cyclosporin A, a macrocyclic lactone that has a structural similarity to the immunosuppressant antibiotic rapamycin. The synthetic studies proposed here entail the construction of these immunosuppressants, initially FK-506, by a convergent pathway in which the dicarbonyl amide lift side portion if united with the masked alpha-allylaldol right side portion and finally macrolactamization is achieved. This strategy provides for the facile formation of structural variations through late stage change in the linking units as well as through independent substantive structural changes in the left and right portions.

建议研究FK-506的免疫抑制活性， 其结构类似物，通过发展有效的收敛 合成，然后进行生物测试。 最初的具体目标是 工作将是FK-5506的合成，以建立合成 战略和方法。 设计合成方法的目的是， 可以进行长距离的结构修改， 配置类似物以测试结构要求 免疫抑制 第一个临床使用的免疫抑制剂，环孢菌素A， 彻底改变了器官移植疗法 一种肽，环孢菌素A和 人们已经合成了许多类似物，并研究了它们的生物活性 研究了 最近发现的FK-506是一种活性更强的免疫抑制剂 不同的抗生素，副作用少。 相比之下，FK-506 环孢菌素A是一种大环内酯，其结构与 免疫抑制抗生素雷帕霉素。 提出的综合研究 这里需要构建这些免疫抑制剂，最初是FK-506， 通过会聚路径，其中二羰基酰胺提升侧部分， 与掩蔽的α-烯丙基醛醇右侧部分结合， 实现大环内酰胺化。 这一战略提供了简便的 通过连接的后期变化形成结构变化 以及通过独立的实质性结构改革， 左部和右部。