title: Microwave-assisted solid-phase aza-peptide synthesis: aza scan of a PKB/Akt inhibitor using aza-arginine and aza-proline precursors.
abstract: Aza-peptides are peptidomimetics in which one or more of the α-carbons, bearing the side-chain residues, has been replaced by a nitrogen.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.
authors.affiliation: Institute of Chemistry, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Noam S
authors.initials: NS
authors.lastname: Freeman
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.forename: Shoshana
authors.initials: S
authors.lastname: Klein
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D001372:Aza Compounds / Q000737:chemistry*; D005449:Fluorenes / Q000737:chemistry; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry; D008872:Microwaves; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C496789:9-fluorenylmethoxycarbonyl; D001372:Aza Compounds; D005449:Fluorenes; C550755:H-Arg-Pro-Arg-Nva-Tyr-Dap-Hol-NH2; D006834:Hydrazines; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C029424:hydrazine; D001120:Arginine; D011392:Proline; D051057:Proto-Oncogene Proteins c-akt