Synthesis and FKBP binding of small molecule mimics of the tricarbonyl region of FK506

Small acyclic model compounds were synthesized to examine the importance of the C(9) carbonyl group of KF506 for FKBP binding. 4-(4′-Methoxyphenyl)-1-butyl (3″, 4″, 5″-trimethoxyphenylglyoxyl) pipecolate (compound 2d), containing the N-(glyoxyl)pipecolate motif of FK506, was found to bind to FKBP wi...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 4; no. 9; pp. 1161 - 1166
Main Authors Wang, Gary T., Lane, Ben, Fesik, Stephen W., Petros, Andrew, Luly, Jay, Krafft, Grant A.
Format Journal Article
LanguageEnglish
Published Oxford Elsevier Ltd 05.05.1994
Elsevier
Subjects
Biological and medical sciences
Immunomodulators
Medical sciences
Pharmacology. Drug treatments
Binding protein
Biological fixation
Peptides
Structure activity relation
Active site
Immunosuppressive agent
Chemical synthesis
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Summary:Small acyclic model compounds were synthesized to examine the importance of the C(9) carbonyl group of KF506 for FKBP binding. 4-(4′-Methoxyphenyl)-1-butyl (3″, 4″, 5″-trimethoxyphenylglyoxyl) pipecolate (compound 2d), containing the N-(glyoxyl)pipecolate motif of FK506, was found to bind to FKBP with IC 50 of 16 μM. Replacement of the carbonyl group at the position corresponding to C(9) of FK506 with small nonpolar groups (hydrogen, methylene or methyl group, compounds 2a–2c) significantly reduced the binding affinity. Small acyclic model compounds, 2a–d, were synthesized to examine the importance of the C(9) carbonyl group of FK506 for FKBP binding
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)80248-1