Submonomer Solid-Phase Synthesis of Aza-Glu Peptides

摘要

Constrained peptide mimics (peptidomimetics) containing glutamate residues have adopted widespread use in medicinal chemistry programs aimed to modulate the activity of target receptors by selective ionic interactions [1]. Azapeptides constitute an important class of constrained peptidomimetics that pre-organize some types of β-tum structures and improve pharmacokinetic properties of bio-active peptides for potential therapeutic applications [2]. An inherent limitation to study the biological activity of azapeptides is the tedious solution phase preparation of the aza-amino acid monomer prior to incorporation within peptide sequences by solid-phase peptide synthesis (SPPS). This is particularly the case in aza-Glu containing azapeptides which required iterative protection and deprotection steps for selectively differentiating the two hydrazine nitrogen atoms prior to the incorporation of the side chain [3]. In order to facilitate the synthesis of azapepetides, we have devised a submonomer method, which builds the aza-residue side chain directly onto the peptide during Fmoc-based solid-phase synthesis [4]. The method is highlighted by the synthesis of aza-Glu containing azapeptides related to the GHRP-6 (i.e. His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) and the D-Thr-D-Glu-D-Glu-D-Glu-D-Gln-D-Tyr-D-Leu sequences.