IMMUNOSUPPRESSANTS--SYNTHESIS OF FK-506

免疫抑制剂--FK-506的合成

• 批准号: 3300513
• 负责人: ROBERT E IRELAND
• 金额: $ 16.29万
• 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/3300513
• 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.

本文拟对FK-506和FK-506的免疫抑制活性进行研究