title: Ring-closing metathesis for the synthesis of side chain knotted pentapeptides inspired by vancomycin.
abstract: A versatile method for the synthesis of bicyclic side chain knotted peptides inspired by vancomycin is described. The synthetic approach is based on the incorporation of a central amino acid derivative having two allylic groups-introduced by a Stille coupling-into pentapeptide 8 containing two allylated serine residues. Treatment of this bis-ring-closing metathesis precursor with 2nd generation Grubbs catalyst results in the formation of a bicyclic pentapeptide with the correct side chain to side chain connectivity pattern as observed in vancomycin: i- 2 --> i, i --> i + 2. Modelling studies using MacroModel hint at a cavity-like structure of the bicyclic pentapeptide which may bind suitable ligands.
authors.affiliation: Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Hefziba T
authors.initials: HT
authors.lastname: ten Brink
authors.forename: Dirk T S
authors.initials: DT
authors.lastname: Rijkers
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.forename: Hans W
authors.initials: HW
authors.lastname: Hilbers
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D003500:Cyclization; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D014640:Vancomycin / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; D014640:Vancomycin