crystal structure analyses of azasulfuryltripeptides reveal potential for γ‐turn mimicry^†

Abstract

Azasulfurylpeptides feature an amino acid residue in which the CαH and the carbonyl are replaced respectively by a nitrogen atom and a sulfonyl group. Insight into the conformational preferences of azasulfurylpeptides containing an azasulfurylglycine (AsG) residue has been pursued using X-ray analysis in the solid state. Crystals of N-(Boc)-Pro-AsG-Val-OMe (10) and N-(Cbz)-Ala-AsG-D-Phe-Ot-Bu (11) showed tetrahedral geometries about the sulfur atom with the ω torsion angle preferring a staggered conformation. Furthermore, the ϕ and ψ torsion angles of the central azasulfuryl residue were respectively within close proximity to those of ideal inverse and classical γ-turns. In the crystal lattice, azasulfurylpeptide 11 engaged in intermolecular hydrogen bonds between the sulfonyl oxygen and hydrazide hydrogen in an antiparallel orientation.

En route towards the peptide γ‐helix: X‐ray diffraction analyses and conformational energy calculations of Adm‐rich short peptides

“…Among the variety of building blocks suggested as efficient γ-turn inducers or mimics (see, for example, refs. [11,[30][31][32][33][34][35]), which might be useful for the construction of γ-helices, we selected the C α -tetrasubstituted, achiral 2-aminoadamantane-2-carboxylic acid (Adm; Figure 2) because of the following: (i) its preparation from the commercially available 2-adamantone [36][37][38][39][40] and (ii) an initial solution investigation by NMR and IR absorption [35] on one derivative, Ac-Adm-NHMe (Ac, acetyl; NHMe, methylamino) and one very short peptide, the terminally blocked dipeptide Ac-Adm-Gly-NHMe, were already reported. In the latter publication, this α-amino acid was proposed as a 'promising γ-turn inducer for synthetic peptides'.…”

Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)

“…N-Aminosulfamide residues differ from their semicarbazide counterparts by the presence of a sulfuryl (SO 2 ) group which adopts tetrahedral geometry and offers two Lewis base sites in contrast to the planar carbonyl group (CO). Compared to azapeptides in which the semicarbazide situates at the central residues of β-turns, model azasulfurylpeptides have been observed to adopt γ-turn conformers in X-ray crystallographic analyses [41]. The replacement of a semicarbazide residue by an N-aminosulfamide counterpart was performed to examine subtle structural and conformational differences on activity.…”

Azasulfurylpeptide Modulation of CD36-Mediated Inflammation Without Effect on Neovascularization

“…Azasulfurylpeptides (e.g., 3 – 6 , Figure 1) are peptides containing an N -aminosulfamide as amino amide surrogate [20,21,22,23,24,25]. Combining semicarbazide [26] and sulfonamide properties [27,28], N -aminosulfamides were shown (by X-ray crystallography) to restrict model peptide backbones to geometry characteristic of the central residues in ideal β- and γ-turns [22]. Cyclic azasulfurylpeptides have served as ligands of the urotensin II receptor (e.g., 4 and 5 ) [23].…”