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Solid-phase synthesis and characterization of N-methyl-rich peptides

Authors

  • M. Teixidó,

    1. M. Teixidó, F. Albericio, E. Giralt, Institut de Recerca Biomèdica de Barcelona, Parc Científic de Barcelona, Josep Samitier, Barcelona, Spain
      F. Albericio and E. Giralt, Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès, Barcelona, Spain
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  • F. Albericio,

    1. M. Teixidó, F. Albericio, E. Giralt, Institut de Recerca Biomèdica de Barcelona, Parc Científic de Barcelona, Josep Samitier, Barcelona, Spain
      F. Albericio and E. Giralt, Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès, Barcelona, Spain
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  • E. Giralt

    1. M. Teixidó, F. Albericio, E. Giralt, Institut de Recerca Biomèdica de Barcelona, Parc Científic de Barcelona, Josep Samitier, Barcelona, Spain
      F. Albericio and E. Giralt, Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès, Barcelona, Spain
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Prof. Ernest Giralt
Institut de Recerca Biomèdica de Barcelona
Parc Científic de Barcelona
Josep Samitier
1-5. E-08028 Barcelona
Spain
Tel.: (34) 93 4037125
Fax: (34) 93 4037126
E-mail: egiralt@pcb.ub.es

Abstract

Abstract:  A library of peptides required for a project investigating the factors relevant for blood–brain barrier transport was synthesized on solid phase. As a result of the high N-methylamino acid content in the peptides, their syntheses were challenging and form the basis of the work presented here. The coupling of protected N-methylamino acids with N-methylamino acids generally occurs in low yield. (7-azabenzotriazol-1-yloxy)-tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) or PyBOP/1-hydroxy-7-azabenzotriazole (HOAt), are the most promising coupling reagents for these couplings. When a peptide contains an acetylated N-methylamino acid at the N-terminal position, loss of Ac-N-methylamino acid occurs during trifluoroacetic acid (TFA) cleavage of the peptide from the resin. Other side reactions resulting from acidic cleavage are described here, including fragmentation between consecutive N-methylamino acids and formation of diketopiperazines (DKPs). The time of cleavage is shown to greatly influence synthetic results. Finally, high-performance liquid chromatography (HPLC) profiles of N-methyl-rich peptides show multiple peaks because of slow conversion between conformers.

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