Retention of immunosuppressant activity in an ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12.

Wiedeman PE, Fesik SW, Petros AM, Nettesheim DG, Mollison KW, Lane BC, Or YS, Luly JR
J Med Chem. 1999 42 (21): 4456-61

PMID: 10543889 · DOI:10.1021/jm980252z

C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated 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 interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.

MeSH Terms (21)

Amino Acid Sequence Animals Humans Hyperplasia Immunophilins Immunosuppressive Agents Lymph Nodes Lymphocyte Culture Test, Mixed Magnetic Resonance Spectroscopy Male Models, Molecular Molecular Sequence Data Nucleotidyltransferases Peptidylprolyl Isomerase Protein Binding Rats Rats, Inbred Lew Rats, Sprague-Dawley Recombinant Fusion Proteins Tacrolimus Tacrolimus Binding Proteins

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