Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to sidechain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of CuI-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(N3) or the incorporation of Fmoc-Nle(N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase CuI-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(N3)-Ser-Ile-Gln-Pra-Leu-Arg-NH2 (2) into the 1,4-disubstituted [1,2,3]triazolylcontaining cyclopeptide [Ac-Lys-Gly-Xaa(&1)-Ser-Ile-Gln-Yaa(&2)-Leu-Arg-NH2][(&1(CH2)4-1,4- [1,2,3]triazolyl-CH2&2)] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys13(&1),Asp17(&2)]hPTHrP(11-19)NH2 (II). CD and NMR studies of 3 and II in water/ hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.

Synthesis and Conformational Analysis of a Cyclic Peptide Obtained via i-to-i+4 Intramolecular Side-Chain-to-Side-Chain Azide–Alkyne 1,3-Dipolar Cycloaddition / S. Cantel; A. Le Chevalier-Isaad; M. Scrima; J. Levy; R. DiMarchi; P. Rovero; J. Halperin; A. D'Ursi; A.M. Papini; M. Chorev. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - STAMPA. - 73:(2008), pp. 5663-5674.. [10.1021/jo800142s]

Synthesis and Conformational Analysis of a Cyclic Peptide Obtained via i-to-i+4 Intramolecular Side-Chain-to-Side-Chain Azide–Alkyne 1,3-Dipolar Cycloaddition.

ROVERO, PAOLO;PAPINI, ANNA MARIA;
2008

Abstract

Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to sidechain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of CuI-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(N3) or the incorporation of Fmoc-Nle(N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase CuI-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(N3)-Ser-Ile-Gln-Pra-Leu-Arg-NH2 (2) into the 1,4-disubstituted [1,2,3]triazolylcontaining cyclopeptide [Ac-Lys-Gly-Xaa(&1)-Ser-Ile-Gln-Yaa(&2)-Leu-Arg-NH2][(&1(CH2)4-1,4- [1,2,3]triazolyl-CH2&2)] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys13(&1),Asp17(&2)]hPTHrP(11-19)NH2 (II). CD and NMR studies of 3 and II in water/ hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.
2008
73
5663
5674.
S. Cantel; A. Le Chevalier-Isaad; M. Scrima; J. Levy; R. DiMarchi; P. Rovero; J. Halperin; A. D'Ursi; A.M. Papini; M. Chorev
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/351094
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