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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041983-03
Application #
3300512
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1990-04-01
Project End
1994-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904