Retention of immunosuppressant activity in an ascomycin analogue lacking ahydrogen-bonding interaction with FKBP12

C24-Deoxyascomycin was prepared in a two-step process from ascomycin and ev aluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, w as likewise evaluated. Despite lacking the hydrogen-bonding interactions as sociated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding in teractions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomen on at the molecular level. The NMR structures of the complexes formed betwe en FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not im portant; for complex formation.