title: Configurational reassignment and improved preparation of the competitive IL-6 receptor antagonist 20R,21R-epoxyresibufogenin-3-formate.
abstract: 20R,21R-Epoxyresibufogenin-3-formate (1) and 20S,21S-epoxyresibufogenin-3-formate (2) were synthesized from commercial resibufogenin (3) using known procedures. The major product (1) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20S,21S-configuration on the basis of NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20R,21R-epoxyresibufogenin-3-formate (1). Our minor synthetic product was determined to have the (-)-20S,21S-configuration (2). The (+)-20R,21R-compound 1 has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of 1 was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of 1, the only known nonpeptide small-molecule IL-6 antagonist.
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, NIDA and NIAAA, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, Maryland 20892-9415, USA.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Boos
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Greiner
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D002018:Bufanolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005561:Formates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: C466795:20,21-epoxyresibufogenin-3-formate; D002018:Bufanolides; D005561:Formates; D019947:Receptors, Interleukin-6; C005734:bufogenin