A Nonpeptidic Reverse-Turn Scaffold Stabilized by Urea-Based Dual Intramolecular Hydrogen Bonding

Abstract

A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained D-prolyl-cis-1,2-diaminocyclohexane (D-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation that is stabilized by dual intramolecular hydrogen bonding in both solution and solid states.

N-Prolinylanthranilamide Pseudopeptides as Bifunctional Organocatalysts for Asymmetric Aldol Reactions

“…In addition, the anilide NH showed a much lower sensitivity to solvent than the valinyl NH (in d 6 -DMSO: δ10.88 [Δδ = 0.15] vs, 7.8 [Δδ = 1.3], respectively). We observed small dependence of the anilide NH chemical shift on temperature in 20% DMSO in chloroform, also consistent with this hydrogen bonding motif . A linear shift to a lower field was observed as the temperature was decreased, with a temperature coefficient (Δδ/Δ T ) of 4.6 ppb/K for the anilide NH(A) versus 10.2 ppb/K for the valinyl NH(B) (see Figure for NH labeling). , These observations support the proposed intramolecular hydrogen bonding for NH(A) but not NH(B), as depicted in Figure A.…”

Rapid access to reverse-turn peptidomimetics by a three-component Ugi reaction of 3,4-dihydroisoquinoline

“…For compound 1c, values of Δδ/ΔT corresponding to -7.7 ppb/K for N 1 H and -6.3 ppb/K for N 2 H were measured. Similarly, for compound 1f the detected values of Δδ/ΔT were -6.1 ppb/K for N 1 H and -5.4 ppb/K for N 2 H. According to literature, [40][41][42][43] these values are in agreement with the presence of intramolecular hydrogen bonds, thus supporting the presence of stabilized secondary structures. Figure 3 shows the structures of compounds 1c, (S,S)-1f, and (R,S)-1f as obtained from the calculations.…”

The Role of N‐Methyl Squaramides in a Hydrogen‐Bonding Strategy to Fold Peptidomimetic Compounds

“…However, small peptides rarely retain their parent conformation and have poor pharmacokinetic properties. The use of peptidomimetics with engineered structural elements that act as macrocyclic scaffolds and turn modules becomes fundamental to control the secondary structure of the synthetic analogues and enhance peptide stability against peptidases …”

“…[4][5][6] However, small peptides rarely retain their parentc onformationa nd have poor pharmacokinetic properties. Theu se of peptidomimetics with engineered structural elements [7,8] that act as macrocyclic scaffolds [9] and turn modules [10] becomesf undamental to control the secondary structure of the synthetic analogues and enhancepeptide stabilitya gainst peptidases. [11] Amongs econdaryp rotein structures, b-turns have drawn much attention because of their crucial role in the bioactive peptidec onformation, [12] the formation of b-sheets and protein-protein interactions.…”

“…However, most of them, based on cyclic or polycyclics tructures, substitute the hydrogen bond found in natural peptides by ac ovalent bond. [17] Nevertheless,t here are fewer exampleso fh ydrogen-bond driven turn modules that efficiently fold linear peptomimetic structures, because there are al imited number of organic building blocks that provide the required conformationalc ontrol, such as modified amino acids, [18][19][20] lactams, [21,22] ureas, [10,23] and thioureas, [24] among others. Thus, the development of theset ype of modules remains achallengingi ssue.…”