title: Anchimeric assistance effect on regioselective hydrolysis of branched PEGs: a mechanistic investigation.
abstract: Branched poly(ethylene glycols) (PEG2) are nowadays widely used for protein and peptides bioconjugation, for their favourable properties (such as the ability to protect the protein surface in an 'umbrella like' fashion). The discovery that mPEG(2)-LysMetbeta AlaOEt lost one mPEG chain during standard base-catalysed ester hydrolysis conditions prompted us to investigate the hydrolytic stability of such systems and the mechanism involved in the PEG chain loss. A series of branched PEGs, substituted with different aminoacids and dipeptides, have been prepared to test the influence of steric hindrance, chain lengths, ramification and Lys-AA amide substitution on hydrolysis. Unexpected results reveal an anchimeric assistance of the Lys-AaA amide proton to the hydrolysis of the carbamoyl moiety joining mPEG to the alpha-amino group of lysine through the formation of an hydantoin system.
authors.affiliation: Dipartimento di Science Farmaceutiche, Via Marzolo, 5, 35131 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guiotto
authors.forename: Mirta
authors.initials: M
authors.lastname: Canevari
authors.forename: Michela
authors.initials: M
authors.lastname: Pozzobon
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Piero
authors.initials: P
authors.lastname: Orsolini
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Veronese
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry; D004355:Drug Stability; D006868:Hydrolysis; D008239:Lysine / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D011092:Polyethylene Glycols; D008239:Lysine