Two consecutive aza-amino acids in peptides promote stable β-turn formation in water

Abstract

Studies on the synthetic methodologies and the structural propensity of peptides containing consecutive aza-amino acids are still in their infancy. Here, the synthesis and conformational analysis of tripeptides containing two...

Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein–Protein Interactions and Act as Natural Chaperones

“…The substitution of the α-CH of one amino-acid residue by a nitrogen atom has already provided biologically active peptides, such as Goserelin approved for the treatment of prostate cancer and having an aza-Gly residue at its C-terminus. – However, the introduction of two or more aza-amino acids in peptide sequences has not been studied both for the influence on the induced conformational properties and for the potential as biologically active peptidomimetic foldamers. We have recently developed the synthesis in the solution of pseudotripeptides having two consecutive aza-amino acids, and we demonstrated the formation of stable hydrogen-bonded β-turn structures of these units both in methanol and in water. , A first pseudohexapeptide foldamer aza-Val/aza-Ala/α-Val/aza-Val/aza-Ala/α-Val was shown to adopt repeated β-turn conformations that interconvert with a fully helical structure mimicking a 3 10 helix in methanol . Here, we further investigate the conformational propensities of longer foldamers having one, two, or three diaza-peptide units in different positions and combinations.…”

“…We have recently developed the synthesis in the solution of pseudotripeptides having two consecutive aza- amino acids, 17 and we demonstrated the formation of stable hydrogen-bonded β-turn structures of these units both in methanol and in water. 18,19 A first pseudohexapeptide foldamer aza-Val/aza-Ala/α-Val/aza-Val/aza-Ala/α-Val was shown to adopt repeated β-turn conformations that interconvert with a fully helical structure mimicking a 3 10 helix in methanol. 18 Here, we further investigate the conformational propensities of longer foldamers having one, two, or three diaza-peptide units in different positions and combinations.…”

1,3,5,8-Tetrasubstituted 1,3,4-Benzotriazepin-2-one Scaffolds for β-Turn Mimicry without Stereogenic Carbon Centers: Synthesis and Conformational Analysis

“…The mixture was washed with H 2 O (5 × 50 mL), dried (MgSO 4 ), filtered, and evaporated to a residue that was purified by chromatography (0−30% EtOAc in hexanes). Evaporation of the collected fractions gave benzotriazepinone 21 as a yellow oil (1.6 g, 63%): R f 0.61 (30% EtOAc in hexanes); 1 [1,2,4]triazepine-8-carboxylic Acid (22). A solution of benzotriazepinone 21 (360 mg, 0.548 mmol) in 25% TFA in CH 2 Cl 2 (10 mL) was stirred for 4 h. The volatiles were removed under the reduced pressure to afford acid 22 as a dark red oil (374 mg, 99%), which was used for the next step without further purification: 1…”

“…Considering the presence of a stereogenic carbon center adds cost to the drug production process in terms of additional analytical and potential separation expenses, , achiral β-turn mimics are interesting potentially economically valuable targets. In this light, two consecutive aza-amino acid residues have been shown to favor type I β-turn conformations in model peptides. , In the present report, the functionalization of the 8-position of the benzotriazepine scaffold has been pursued to provide a small molecule scaffold that offers comparable orientations of side chain pharmacophores as those in benzodiazepinone 3 for β-turn mimicry.…”

“…In this light, two consecutive aza-amino acid residues have been shown to favor type I β-turn conformations in model peptides. 21,22 In the present report, the functionalization of the 8-position of the benzotriazepine scaffold has been pursued to provide a small molecule scaffold that offers comparable orientations of side chain pharmacophores as those in benzodiazepinone 3 for β-turn mimicry.…”