title: Analogs of cyclosporin A modified at the D-Ala8 position.
abstract: The conversion of [2-deutero-3-fluoro-D-Ala8]cyclosporin A (1) to a dehydroalanine analog [delta-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.
authors.affiliation: Merck, Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
authors.forename: D
authors.initials: D
authors.lastname: Taub
authors.forename: O D
authors.initials: OD
authors.lastname: Hensens
authors.forename: R T
authors.initials: RT
authors.lastname: Goegelman
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: F
authors.initials: F
authors.lastname: Dumont
authors.forename: L
authors.initials: L
authors.lastname: Peterson
authors.forename: N H
authors.initials: NH
authors.lastname: Sigal
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003524:Cyclosporins / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D003524:Cyclosporins; D007166:Immunosuppressive Agents