IMMUNOSUPPRESSANTS--SYNTHESIS OF FK-506

免疫抑制剂--FK-506的合成

• 批准号: 3300511
• 负责人: ROBERT E IRELAND
• 金额: $ 15.3万
• 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/3300511
• 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 和 FK-506 的免疫抑制剂活性 通过开发高效收敛的结构类似物 合成然后进行生物测试。 本次活动最初的具体目标 工作将是合成 FK-5506，以便建立合成 策略和方法。 合成方法的设计使得， 可以进行长范围的结构修改，从而产生 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是环孢菌素A 彻底改变了器官移植疗法。 A肽、环孢菌素A和 已经合成了许多类似物及其生物活性 研究过。 最近发现的 FK-506 是一种活性更强的免疫抑制剂 抗生素具有不同且副作用更少。 相比之下，FK-506 环孢菌素 A 是一种大环内酯，其结构与 免疫抑制剂抗生素雷帕霉素。 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， 通过收敛路径，其中二羰酰胺提升侧部分如果 与蒙面α-烯丙醛右侧部分结合，最后 实现大环内酰胺化。 该策略提供了便利 通过连接的后期变化形成结构变异 单位以及通过独立的实质性结构变化 左部分和右部分。