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Aza-peptides are peptidomimetics in which one or more of the α-carbons, bearing the side-chain residues, has been replaced by a nitrogen.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.

Facile Synthesis of Guanidine Functionalised Building Blocks

“…Similarly, hydroxypropylguanidine 18 (only commercially available from specialty suppliers) [26] was synthesised in good yield (81%, Table 2, entry 2) using 3-amino-1-propanol and its isolation was easy following only an aqueous extraction. [27] 22 (81) [a] Reaction was carried out over 5 hours.…”

A Review on Azapeptides: The Promising Peptidomimetics

“…Complete substitution of all asymmetric substituted α-carbons is represented by pure azapeptides termed azatides [13]. The aza scan of a potent peptide based PKB/AKt inhibitor was reported using aza-arginine and aza-proline precursors [14].…”

Amino acid chlorides: a journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics

“…al. followed similar procedure with due modifications for a microwave assisted solid-phase aza-peptide synthesis 288. The application of microwaves reduced the standard reaction time and lead to efficient coupling of the aza-amino acid to the growing peptide and next amino acid coupling to the aza residue.…”