IMMUNOSUPPRESSANTS--SYNTHESIS OF FK-506

免疫抑制剂--FK-506的合成

• 批准号: 3300512
• 负责人: ROBERT E IRELAND
• 金额: $ 15.92万
• 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/3300512
• 关键词: biological products; 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的免疫抑制活性和 其结构类比通过开发高效收敛来实现 先是合成，然后是生物测试。这个项目最初的具体目标是 工作将是合成FK-5506，以建立合成 战略和方法论。综合方法的设计是为了，在 可以进行长期的、结构性的修改，以产生 为测试结构要求而配置的模拟器 免疫抑制。 第一种临床使用的免疫抑制剂，环孢素A，已经 革命性的器官移植疗法。A肽、环孢菌素A和 已经合成了许多类似物，它们的生物活性 学习。最近发现的FK-506是一种更活跃的免疫抑制剂 具有不同和更少副作用的抗生素。相比之下，FK-506 环孢素A，结构类似于环孢素A的大环内酯 免疫抑制抗生素雷帕霉素。综合研究建议 这里需要构建这些免疫抑制剂，最初是FK-506， 通过收敛路径，在该收敛路径中，二甲酰胺提升侧部IF 与面膜的α-烯丙醛右侧部分结合，最后 实现了大范围内酰胺化。这种策略提供了便捷的 通过连接作用的后期变化形成构造变化 以及通过独立的实质性结构改革 左边和右边的部分。