The recently introduced Cu(I)-catalyzed azide–alkyne 1,3-dipolar Huisgen cycloaddition as a prototypic “click chemistry reaction” presented an opportunity for introducing the 1,4-disubstituted-[1,2,3]triazolyl moiety as a new isostere for peptide bonds in the backbone. Previous study in our lab focused on the synthesis of a model i-to-i+4 side chain-to-side chain 1,4- and 4,1-disubstituted-[1,2,3]triazolyl-bridged cyclo-nonapeptide I (Scheme 1) as analogues of its structurally related helical i-to-i+4 lactam-bridged cyclo-nonapeptide [Lys13(& 1),Asp17(& 2)]parathyroid hormone related peptide (PTHrP)(11–19)NH21 a truncated version of the α-helical and potent parathyroid hormone receptor 1 agonist [Lys13(& 1),Asp17(& 2)]PTHrP(1-34)NH2,2,3 Nα-Ac-Lys-Gly-Lys(& 1)-Ser-Ile-Gln-Asp(& 2)-Leu-Arg-NH2]. Systematic [1,2,3]triazolyl-containing bridge structure–conformation relationship studies in hexafluoroacetone/water mixture included incorporation of bridges varied in size and position and orientation of the triazolyl ring within the bridge. These studies revealed that the size of methylene bridge flanking triazolyl moiety is critical to reproduce in the heterodetic cyclo-nonapeptides. The conformational features of the analogues cyclo-nonapeptide in which Lys13 and Asp17 are bridged by the isosteric lactam. Here, we extend our conformational analysis to dimethyl sulfoxide/water mixture in an effort to characterize inherent conformational properties of the heterodetic cyclopeptides that are solvent independent. Our present study shows that the physicochemical properties of the structure-supporting solvent cannot override the effect of the size of methylene bridge to form helical mimetic structures. Moreover, we prove that [1,2,3]triazolyl ring is not a simple bioisostere of lactam bond, but it affects the secondary structure of the peptide, in relation to its positioning orientation

Solvent independent conformational propensities of [1,2,3]triazolyl-bridged PTHrP-derived cyclo-nonapeptide analogues

SCRIMA, MARIO;GRIMALDI, MANUELA;DI MARINO, SARA;D'URSI, Anna Maria
2012

Abstract

The recently introduced Cu(I)-catalyzed azide–alkyne 1,3-dipolar Huisgen cycloaddition as a prototypic “click chemistry reaction” presented an opportunity for introducing the 1,4-disubstituted-[1,2,3]triazolyl moiety as a new isostere for peptide bonds in the backbone. Previous study in our lab focused on the synthesis of a model i-to-i+4 side chain-to-side chain 1,4- and 4,1-disubstituted-[1,2,3]triazolyl-bridged cyclo-nonapeptide I (Scheme 1) as analogues of its structurally related helical i-to-i+4 lactam-bridged cyclo-nonapeptide [Lys13(& 1),Asp17(& 2)]parathyroid hormone related peptide (PTHrP)(11–19)NH21 a truncated version of the α-helical and potent parathyroid hormone receptor 1 agonist [Lys13(& 1),Asp17(& 2)]PTHrP(1-34)NH2,2,3 Nα-Ac-Lys-Gly-Lys(& 1)-Ser-Ile-Gln-Asp(& 2)-Leu-Arg-NH2]. Systematic [1,2,3]triazolyl-containing bridge structure–conformation relationship studies in hexafluoroacetone/water mixture included incorporation of bridges varied in size and position and orientation of the triazolyl ring within the bridge. These studies revealed that the size of methylene bridge flanking triazolyl moiety is critical to reproduce in the heterodetic cyclo-nonapeptides. The conformational features of the analogues cyclo-nonapeptide in which Lys13 and Asp17 are bridged by the isosteric lactam. Here, we extend our conformational analysis to dimethyl sulfoxide/water mixture in an effort to characterize inherent conformational properties of the heterodetic cyclopeptides that are solvent independent. Our present study shows that the physicochemical properties of the structure-supporting solvent cannot override the effect of the size of methylene bridge to form helical mimetic structures. Moreover, we prove that [1,2,3]triazolyl ring is not a simple bioisostere of lactam bond, but it affects the secondary structure of the peptide, in relation to its positioning orientation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/3879971
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