Microwave-Assisted Solid-Phase Aza-peptide Synthesis: Aza Scan of a PKB/Akt Inhibitor Using Aza-arginine and Aza-proline Precursors

Aza-peptides are peptidomimetics in which one or more of the alpha-carbons, bearing the side-chain residues, has been replaced by a nitrogen. These peptidomimetics have been shown to be promising for the generation of drug leads and for structure-activity relationship studies. Aza-scan is the systematic replacement of amino acid residues in a given peptide with their aza counterparts. We report here an aza-scan of a potent, peptide-based PKB/Akt inhibitor, PTR6154. Procedures for microwave-assisted, Fmoc/t-Bu chemistry, solid-phase aza-peptide synthesis were developed which significantly reduce standard reaction time and are suitable for automation. Novel substituted hydrazines have been prepared for the straightforward incorporation of aza-arginine and aza-proline residues. This work will enable aza-scan to become a more common and standard method for structure-activity relationship studies of peptides.