Synthesis of orthogonally reactive FK506 derivatives via olefin cross metathesis.
Chemical inducers of dimerization (CIDs) are employed in a wide range of biological applications to control protein localization, modulate protein-protein interactions and improve drug lifetimes. These bifunctional chemical probes are assembled from two synthetic modules, which each provide affinity for a distinct protein target. FK506 and its derivatives are often employed as modules in the syntheses of these bifunctional constructs, owing to the abundance and favorable distribution of their target, FK506-binding protein (FKBP). However, the structural complexity of FK506 necessitates multi-step syntheses and/or multiple protection-deprotection schemes prior to installation into CIDs. In this work, we describe an efficient, one-step synthesis of FK506 derivatives through a selective, microwave-accelerated, cross metathesis diversification step of the C39 terminal alkene. Using this approach, FK506 is modified with an array of functional groups, including primary amines and carboxylic acids, which make the resulting derivatives suitable for the modular assembly of CIDs. To illustrate this idea, we report the synthesis of a heterobifunctional HIV protease inhibitor.
Marinec
Paul S
PS
Department of Pathology and The Life Sciences Institute, University of Michigan, Ann Arbor, 48109, USA.
Evans
Christopher G
CG
Gibbons
Garrett S
GS
Tarnowski
Malloree A
MA
Overbeek
Daniel L
DL
Gestwicki
Jason E
JE
D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism; D002384:Catalysis; D019281:Dimerization; D017320:HIV Protease Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008872:Microwaves; D012428:Ruthenium / Q000737:chemistry; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000737:chemistry; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism
D000475:Alkenes; D017320:HIV Protease Inhibitors; D007166:Immunosuppressive Agents; D012428:Ruthenium; D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus