Ring-closing metathesis for the synthesis of side chain knotted pentapeptides inspired by vancomycin.
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.
ten Brink
Hefziba T
HT
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
Rijkers
Dirk T S
DT
Kemmink
Johan
J
Hilbers
Hans W
HW
Liskamp
Rob M J
RM
D003500:Cyclization; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D014640:Vancomycin / Q000737:chemistry*
D009842:Oligopeptides; D014640:Vancomycin