A backbone amide protecting group for overcoming difficult sequences and suppressing aspartimide formation.

Autor: Abdel-Aal AB; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK., Papageorgiou G; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK., Raz R; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK., Quibell M; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK., Burlina F; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.; Sorbonne Universités, UPMC Université Paris 06, LBM, 4 place Jussieu, 75005, Paris, France.; CNRS, UMR 7203, LBM, Paris, France.; Département de Chimie, LBM, ENS, PSL Research University, 24 Rue Lhomond, 75005, Paris, France., Offer J; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
Jazyk: angličtina
Zdroj: Journal of peptide science : an official publication of the European Peptide Society [J Pept Sci] 2016 May; Vol. 22 (5), pp. 360-7. Date of Electronic Publication: 2016 Apr 18.
DOI: 10.1002/psc.2877
Abstrakt: A backbone amide bond protecting group, 2-hydroxy-4-methoxy-5-nitrobenzyl (Hmnb), improved the synthesis of aggregation and aspartimide-prone peptides. Introduction of Hmnb is automated and carried out during peptide assembly by addition of 4-methoxy-5-nitrosalicylaldehyde to the peptidyl-resin and on-resin reduction to the secondary amine. Acylation of the hindered secondary amine is aided by the formation of an internal nitrophenol ester that undergoes a favourable O,N intramolecular acyl transfer. This activated ester participates in the coupling and generally gives complete reaction with standard coupling conditions. Hmnb is easily available in a single preparative step from commercially available material. Different methods for removing the amide protecting group were explored. The protecting group is labile to acidolysis, following reduction of the nitro group to the aniline. The two main uses of backbone protection of preventing aspartimide formation and of overcoming difficult sequences are demonstrated, first with the synthesis of a challenging aspartimide-prone test sequence and then with the classic difficult sequence ACP (65-74) and a 23-mer homopolymer of polyalanine.
(Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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