David Norman Hardern

Synthesis and evaluation of dual domain macrocyclic FKBP12 ligands.

Abstract A number of dual domain, macrocyclic FKBP12 ligands were synthesised in which the FK506 effector domain was fused to simplified FKBP12 bindings domains. The resulting macrocyclic compounds possessed moderate binding affinities for FKBP12 but showed no activity in an assay for FKBP12 dependent calcineurin inhibition.

Synthetic FKBP12 ligands. Design and synthesis of pyranose replacements.

Abstract A number of FKBP12 ligands were designed and synthesised and their affinity for FKBP12 assessed. In these ligands the pyranose ring of FK506 was replaced by other more synthetically accessible groups. The preparation of suitable intermediates for the synthesis of “dual domain” inhibitors (compounds 6a–c, 15 and 22) is also described.