Building blocks pour la synthèse de peptides "clikables"

In collaboration with:
The Department of Pharmaceutical Sciences, University of Salerno, Italy
The Laboratory for Translational Research, Harvard Medical School, Boston, USA
The Department of Medicine, Brigham and Women’s Hospital, Boston, USA

Azido and Alkynyl amino Acids as Building Blocks for the Synthesis of “Clickable” Peptides

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 side-chain modification and do not require orthogonal protection schemes, are of great interest.

In this context we developed the synthesis of Nα-Fmoc-Protected ω-Azido- and ω-Alkynyl-L-amino Acids as Building Blocks for the Synthesis of “Clickable” Peptides.

Moreover we studied the employment of CuI-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and we  investigated  alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]-triazolyl-containing cyclopeptides.

 In order to investigate if the bioorthogonal i-to-(i+4) side-chain-to-side-chain cyclization via the prototypic “click reaction” offers a new approach for generating stable helix mimetic structures, we performed a comprehensive conformational analysis employing CD, NMR, and molecular dynamics on several heterodetic cyclo-nonapeptides.

Solvent independent conformational propensities of [1,2,3]triazolyl-bridged parathyroid hormone-related peptide-derived cyclo-nonapeptide analogues. Scrima, M.; Grimaldi, M.; Di Marino, S.; Testa, C.; Rovero, P.; Papini, A. M.; Chorev, M.; D’Ursi, A. M. Biopolymers 2012, 98, 535–545. 

Cu I -Catalyzed Azide-Alkyne Intramolecular i-to-(i +4) Side-Chain-to-Side-Chain Cyclization Promotes the Formation of Helix-Like Secondary Structures. Scrima, M.; Le Chevalier-Isaad, A.; Rovero, P.; Papini, A. M.; Chorev, M.; D’Ursi, A. M. Eur. J. Org. Chem. 2010,  446–457.

Side chain-to-side chain cyclization by click reaction. Le Chevalier Isaad, A.; Papini, A. M.; Chorev, M.; Rovero, P. J. Peptide Sci. 2009, 15, 451–454.

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. Cantel, S.; Le Chevalier-Isaad, A.; Scrima, M.; Levy, J. J.; DiMarchi, R. D.; Rovero, P.; Halperin, J. A.; D'Ursi, A. M.; Papini, A. M.; Chorev, M. J. Org. Chem. 2008, 73, 5663-5674.

N-α-Fmoc-Protected ω-Azido- and ω-Alkynyl-L-amino Acids as Building Blocks for the Synthesis of “Clickable” Peptides. Le Chevalier Isaad, A.; Barbetti, F.; Rovero, P.; D’Ursi, A. M.; Chelli, M.; Chorev, M.; Papini, A. M. Eur. J. Org. Chem. 2008, 5308–5314.