Abstract:A comparative conformational analysis of two short pseudopeptides with ETB receptor affinity has been performed by molecular modelling and NMR techniques. This analysis aimed to get insight into probable biorelevant conformations and pharmacophoric patterns necessary for an efficient interaction with the receptor. Thus, it was shown that the two compounds can adopt y-turn (or y-turn-like) conformations, based on which the synthesis of particular, more rigid analogs might be proposed. The results obtained shoul… Show more
“…4 Although γ-turns are less frequent than β-turns, an analysis of 54 proteins from the Protein Data Bank has shown the presence of 12 classic and 117 inverse γ-turns, frequently forming part of higher secondary structures such as loops, β-sheets, or R-helices. 3,5 Furthermore, it has been proposed that γ-turns are present in the solution conformation of several peptides, including vasopresin, 6,7 cyclosporin, 8 angiotensin II, 9,10 bombesin, 11 endothelin antagonists, 12 bradykinin, 13 and the RGD tripeptide sequence in several fibrinogen and integrin antagonists. [14][15][16][17][18][19] Several structural motifs have been described to stabilize or mimic γ-turn conformations, including 1-aminocycloalkane carboxylic acids, 20,21 cis-4-amino-L-proline derivatives, 22 cyclic β-enamino nitriles, 23 tetrahydro-1Hazepine derivatives, 10,14,17,24 hexahydro-1,4-diazepines, 25 cyclic hydrazide derivatives, 26 morpholin-3-ones, 7 (3aminomethyl-2-oxo-1-piperidyl)acetic acid, 13 and 1,3,5trisubstituted-cyclohexanes.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast, inverse γ-turns are characterized by a φ i +1 angle of −9° to −110° (mean value −79°) and a ψ i +1 angle of 14° to 131° (mean value 69°), and the side chain of the i +1 residue in a pseudoequatorial orientation (C 7 equatorial) . Although γ-turns are less frequent than β-turns, an analysis of 54 proteins from the Protein Data Bank has shown the presence of 12 classic and 117 inverse γ-turns, frequently forming part of higher secondary structures such as loops, β-sheets, or α-helices. , Furthermore, it has been proposed that γ-turns are present in the solution conformation of several peptides, including vasopresin, , cyclosporin, angiotensin II, , bombesin, endothelin antagonists, bradykinin, and the RGD tripeptide sequence in several fibrinogen and integrin antagonists. − 1 Schematic description of classic and inverse γ-turns and the mimetic 1 .…”
2-Oxopiperazine derivatives 1 have been designed as mimetics of gamma-turn conformationally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C(5) involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle(31)]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a gamma-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.
“…4 Although γ-turns are less frequent than β-turns, an analysis of 54 proteins from the Protein Data Bank has shown the presence of 12 classic and 117 inverse γ-turns, frequently forming part of higher secondary structures such as loops, β-sheets, or R-helices. 3,5 Furthermore, it has been proposed that γ-turns are present in the solution conformation of several peptides, including vasopresin, 6,7 cyclosporin, 8 angiotensin II, 9,10 bombesin, 11 endothelin antagonists, 12 bradykinin, 13 and the RGD tripeptide sequence in several fibrinogen and integrin antagonists. [14][15][16][17][18][19] Several structural motifs have been described to stabilize or mimic γ-turn conformations, including 1-aminocycloalkane carboxylic acids, 20,21 cis-4-amino-L-proline derivatives, 22 cyclic β-enamino nitriles, 23 tetrahydro-1Hazepine derivatives, 10,14,17,24 hexahydro-1,4-diazepines, 25 cyclic hydrazide derivatives, 26 morpholin-3-ones, 7 (3aminomethyl-2-oxo-1-piperidyl)acetic acid, 13 and 1,3,5trisubstituted-cyclohexanes.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast, inverse γ-turns are characterized by a φ i +1 angle of −9° to −110° (mean value −79°) and a ψ i +1 angle of 14° to 131° (mean value 69°), and the side chain of the i +1 residue in a pseudoequatorial orientation (C 7 equatorial) . Although γ-turns are less frequent than β-turns, an analysis of 54 proteins from the Protein Data Bank has shown the presence of 12 classic and 117 inverse γ-turns, frequently forming part of higher secondary structures such as loops, β-sheets, or α-helices. , Furthermore, it has been proposed that γ-turns are present in the solution conformation of several peptides, including vasopresin, , cyclosporin, angiotensin II, , bombesin, endothelin antagonists, bradykinin, and the RGD tripeptide sequence in several fibrinogen and integrin antagonists. − 1 Schematic description of classic and inverse γ-turns and the mimetic 1 .…”
2-Oxopiperazine derivatives 1 have been designed as mimetics of gamma-turn conformationally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C(5) involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle(31)]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a gamma-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.
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