In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures

Abstract

Peptidomimetics containing (S)- or (R)-imidazolidin-2-one-4-carboxylate (Imi) have been obtained by the expedient in-peptide cyclization of (S)- or (R)-α,β-diaminopropionic acid (Dap) residues. These Imi scaffolds behave as proline analogues characterized by a flat structure and a trans-restricted geometry of the preceding peptide bond and induce well-defined secondary structures in a biomimetic environment. While (S)-Imi peptides adopted a γ′-turn conformation, (R)-Imi induced the contemporary formation of a γ-turn and a rare 11-membered H-bonded structure in the 2→4 opposite direction of the sequence, identified as a ε-turn. In order to exploit these Imi scaffolds as general promoters of unusual secondary structures, proteinaceous side chains have been introduced at the N1 position of the five-membered ring, potentially mimicking any residues. Finally, the Imi rings have been equipped with unnatural side chains or with functionalized substituents, which can be utilized as linkers to chemoselectively bind the Imi-peptides onto nanoparticles, biomaterials, or diagnostic probes.

N-Amino-imidazol-2-one (Nai) Residues as Tools for Peptide Mimicry: Synthesis, Conformational Analysis and Biomedical Applications

“…Although the calculated vinyl proton chemical shifts were identical (6.39 ppm) for Nai 33 and triazinone 34, the corresponding carbon chemical shift values were significantly different: 101.7 and 97.3 ppm, respectively. Experimental analysis by 13 C NMR spectroscopy confirmed the imidazole-2-one in all Nai analogues 33a-o, which exhibited vinylproton-bearing carbon chemical shifts of 101.7 ± 2.1 ppm. In addition, X-ray crystallography of N-Cbz-(5-Et)Nai-Phe-NHi-Pr (36) substantiated the imidazole-2-one product.…”

“…6 N-Amino-imidazol-2-one and -imidazolidin-2-one [Nai (4) and Aid (5)] residues are dipeptide surrogates with strong potential for peptide-based drug discovery. 4,[7][8][9][10][11][12][13] Combining the stereo-electronic features of azapeptides (2) with the covalent constraint characteristic of -amino-lactam [Agl, Freidinger-Veber lactam (3)] residues, [14][15][16] Aid and Nai peptides can replicate natural secondary structures by adopting defined backbone and side-chain geometry. 4 Lone pair-lone pair repulsion between the adjacent nitrogen of the N-acyl semicarbazide component of Aid and Nai residues constricts rotation about the -dihedral angle.…”

Fishing in the Toolbox of Cyclic Turn Mimics: a Literature Overview of the Last Decade

“…As an The same group adopted the above synthetic strategy to build flat structure and trans-restricted geometries in tetrapeptides containing cyclic urea Pro-mimics (scaffold 69, Scheme 16). [51] Sequences containing 69 scaffolds were reached by easy cyclization of the related linear sequences 68 containing a α,β-diamino propionic acid residue. Peptides bearing both enantiomers of scaffold 69 in their 2-or 3-position were realized (70 and 71 in Scheme 16).…”

Heterocycles as a Peptidomimetic Scaffold: Solid-Phase Synthesis Strategies

“…Solid-phase synthesis on a Rink Amide MBHA resin via Fmoc SPPS afforded Tpd peptidomimetics 43 in 3–42% yields. De Marco et al presented another example of a mimetic, by developing ( S )- and ( R )-imidazolidin-2-one-4carboxylates (Imi-peptides) on a solid-phase from ( S )- or ( R )-α,β-diaminopropionic acid residues ( 44 , Figure 2 ) [ 38 ]. A two-step procedure for the synthesis of peptidomimetics containing cyclic threonine (cThr) was presented by Sicherl et al [ 39 ].…”