Aza-Amino Acid Scan for Rapid Identification of Secondary Structure Based on the Application of N-Boc-Aza¹-Dipeptides in Peptide Synthesis

Abstract

Azapeptides, peptide analogues in which the alpha-carbon of one or more of the amino acid residues is replaced with a nitrogen atom, exhibit propensity for adopting beta-turn conformations. A general protocol for the synthesis of azapeptides without racemization on solid phase has now been developed by introducing the aza-amino acid residue as an N-Boc-aza(1)-dipeptide. This approach has been validated by the synthesis of six N-Boc-aza(1)-dipeptides and their subsequent introduction into analogues of the C-terminal peptide fragment of the human calcitonin gene-related peptide (hCGRP). By performing an aza-amino acid scan of such antagonist peptides, a set of aza-hCGRP analogues was synthesized to examine the relationship between turn secondary structure and biological activity.

A Review on Azapeptides: The Promising Peptidomimetics

“…In addition, an amino acid scan of biologically active peptides was introduced as a method for identifying biologically active conformations of different proteins [12].…”

“…This could be achieved by any of the possible routes as given in Table-3. A solid-phase synthesis of three aza-, iminoaza-and reduced azapeptides using the Boc-strategy was reported [92]. By performing an aza-amino acid scan of antagonist peptides, a set of aza-hCGRP analogues was synthesized to examine the relationship between turn secondary structure and biological activity [12]. Modified solid phase methods: With an aim to eliminate the hydantoin side product an efficient method utilizing N-2-hydroxy-4-methoxy benzyl (Hmb) reversible amide bond protecting group was adapted to obtain the desired azapeptides in excellent purity and good yields [93].…”

“…• Fmoc/Ddz-strategy: Azaamino acid scanning method • Submonomer solid phase method • Ugi four component method • Chemical ligation method Fmoc/Ddz-strategy: Azaamino acid scanning method: The most common aza-amino acid building blocks prepared for the solid phase synthesis of azapeptides are Fmoc protected N'-alkyl hydrazine and N-Boc-aza-dipeptide fragments as well as N-Fmoc and N-2-(3,5-dimethoxy phenyl)propan-2-yloxycarbonyl (Ddz) protected aza amino acid chlorides [12]. Among these, Fmoc/Ddz-strategies are useful in producing libraries of azapeptides for exploring structural activity relationships with target receptors.…”

Benzophenone semicarbazone protection strategy for synthesis of aza‐glycine containing aza‐peptides

“…Benzophenone hydrazone offered protection from oxadiazolone formation during activation of the hydrazine moiety; however, the choice of activating group was crucial to the stability of the resulting methylidenecarbazate intermediate 10. Phosgene/triphosgene 19,20,23 and carbonyldiimidazole (CDI) 19,21 have been commonly used as activating agents with fluorenylmethyl and tert-butyl carbazates 1 (Figure 2, Y ¼ Z ¼ Cl or imidazole). On the contrary, activation of benzophenone hydrazone 9 with phosgene or CDI produced symmetric urea 13 24 (R ¼ Ph) as the major product (Scheme 1).…”

“…2 In competition with the synthesis of aza-Gly peptide 5, amino amidederived carbamates 3b and isocyanates 4b have been observed to form hydantoins 6, due to intramolecular amide acylation (see Figure 2). 20 Alternatively, activation of carbazate 1 has been used to couple the aza-Gly residue to amino esters or amino amides 2. For example, N-acyl (Boc, Cbz and amide) hydrazine analogs 1 have been treated with aryl chloroformates 2 and carbonyldiimidazole 21 (CDI) to give activated carbamate intermediates 7, which may acylate an amino ester or amide 2 to provide the aza-Gly peptide 5 (see Figure 2).…”