ANALOGS OF CYCLOSPORIN A MODIFIED AT THE D-ALA8 POSITION

The conversion of [2-deutero-3-fluoro-D-Ala8]cyclosporin A (1) to a dehydroalanine analog [Δ-Ala8]cyclosporin A (2) was achieved with lithium diisopropylamide in THF at low temperature. This dehydro compound is a useful intermediate for the preparation of position 8 analogs of cyclosporin A formed f...

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Bibliographic Details
Published in:Journal of antibiotics 1992/01/25, Vol.45(1), pp.94-102
Main Authors: PATCHETT, ARTHUR A., TAUB, DAVID, HENSENS, OTTO D., GOEGELMAN, ROBERT T., YANG, LIHU, DUMONT, FRANCIS, PETERSON, LARRY, SIGAL, NOLAN H.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chromatography, High Pressure Liquid
Chromatography, Thin Layer
Cyclosporins - chemistry
Cyclosporins - pharmacology
Female
Immunomodulators
Immunosuppressive Agents - chemistry
Immunosuppressive Agents - pharmacology
Lymphocyte Activation
Magnetic Resonance Spectroscopy
Medical sciences
Mice
Mice, Inbred C57BL
Molecular Conformation
Pharmacology. Drug treatments
Spectrometry, Mass, Fast Atom Bombardment
T-Lymphocytes - drug effects
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Summary:The conversion of [2-deutero-3-fluoro-D-Ala8]cyclosporin A (1) to a dehydroalanine analog [Δ-Ala8]cyclosporin A (2) was achieved with lithium diisopropylamide in THF at low temperature. This dehydro compound is a useful intermediate for the preparation of position 8 analogs of cyclosporin A formed from it by the conjugate addition of thiol compounds. NMR conformational studies have provided evidence for the restoration of D-stereochemistry in the modified Ala8 residues. The preparation of several of these cyclosporin analogs and their bioactivities are described.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.45.94