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

P E Wiedeman; S W Fesik; A M Petros; D G Nettesheim; K W Mollison; B C Lane; Y S Or; J R Luly

doi:10.1021/jm980252z

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

J Med Chem. 1999 Oct 21;42(21):4456-61. doi: 10.1021/jm980252z.

Authors

P E Wiedeman¹, S W Fesik, A M Petros, D G Nettesheim, K W Mollison, B C Lane, Y S Or, J R Luly

Affiliation

¹ Abbott Laboratories, Pharmaceutical Products Division, 200 Abbott Park Road, Department 47N, Building AP-52N, Abbott Park, Illinois 60064-6217, USA.

PMID: 10543889
DOI: 10.1021/jm980252z

Abstract

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

Amino Acid Sequence
Animals
Humans
Hyperplasia
Immunophilins / chemistry
Immunophilins / genetics
Immunophilins / metabolism*
Immunosuppressive Agents / chemical synthesis*
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / metabolism
Immunosuppressive Agents / pharmacology
Lymph Nodes / drug effects
Lymph Nodes / immunology
Lymph Nodes / pathology
Lymphocyte Culture Test, Mixed
Magnetic Resonance Spectroscopy
Male
Models, Molecular
Molecular Sequence Data
Nucleotidyltransferases / genetics
Peptidylprolyl Isomerase / chemistry
Peptidylprolyl Isomerase / genetics
Peptidylprolyl Isomerase / metabolism*
Protein Binding
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Recombinant Fusion Proteins / metabolism
Tacrolimus / analogs & derivatives*
Tacrolimus / chemical synthesis
Tacrolimus / chemistry
Tacrolimus / metabolism
Tacrolimus / pharmacology
Tacrolimus Binding Proteins

Substances

C24-deoxyascomycin
Immunosuppressive Agents
Recombinant Fusion Proteins
immunomycin
Nucleotidyltransferases
3-deoxy-manno-octulosonate cytidyltransferase
Tacrolimus Binding Proteins
Immunophilins
Peptidylprolyl Isomerase
Tacrolimus