Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin.
The synthesis of 18 N-alpha-FMOC-amino acid glycosides for solid-phase glycopeptide assembly is reported. The glycosides were synthesized either from the corresponding O'Donnell Schiff bases or from N-alpha-FMOC-amino protected serine or threonine and the appropriate glycosyl bromide using Hanessian's modification of the Koenigs-Knorr reaction. Reaction rates of D-glycosyl bromides (e.g., acetobromoglucose) with the L- and D-forms of serine and threonine are distinctly different and can be rationalized in terms of the steric interactions within the two types of diastereomeric transition states for the D/L and D/D reactant pairs. The N-alpha-FMOC-protected glycosides [monosaccharides Xyl, Glc, Gal, Man, GlcNAc, and GalNAc; disaccharides Gal-beta(1-4)-Glc (lactose), Glc-beta(1-4)-Glc (cellobiose), and Gal-alpha(1-6)-Glc (melibiose)] were incorporated into 22 enkephalin glycopeptide analogues. These peptide opiates bearing the pharmacophore H-Tyr-c[DCys-Gly-Phe-DCys]- were designed to probe the significance of the glycoside moiety and the carbohydrate-peptide linkage region in blood-brain barrier (BBB) transport, opiate receptor binding, and analgesia.
Mitchell
S A
SA
Department of Chemistry, The University of Arizona, Tucson, Arizona 85721, USA.
Pratt
M R
MR
Hruby
V J
VJ
Polt
R
R
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D004220:Disulfides / Q000138:chemical synthesis; D004745:Enkephalins / Q000138:chemical synthesis*; D005449:Fluorenes / Q000737:chemistry; D006023:Glycoproteins / Q000138:chemical synthesis; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry; D006031:Glycosylation; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis; D012545:Schiff Bases / Q000737:chemistry
D000596:Amino Acids; D004220:Disulfides; D004745:Enkephalins; D005449:Fluorenes; D006023:Glycoproteins; D006027:Glycosides; D006842:Hydrocarbons, Brominated; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D012545:Schiff Bases