Projects / Synthetic strategies / Synthetic building-blocks

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

Profiles

In collaboration with:

Department of Medicine, Brigham and Women’s Hospital, Boston,  and Laboratory for Translational Research, Harvard Medical School, Cambridge, USA

Michael Chorev and Jose A. Halperin

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States

Carrie Haskell-Luevano

The Department of Pharmaceutical Sciences, University of Salerno, Italy

Anna Maria D'Ursi

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.

 

Publications

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

A. Le Chevalier Isaad, F. Barbetti, P. Rovero, A.M. D’Ursi, M. Chelli, M. Chorev, and A.M. Papini. N(alpha)-Fmoc-Protected omega-Azido and omega-Ynoic-alpha-Amino Acids as Building Blocks for the Synthesis of "Clickable" Peptides. Eur. J. Org. Chem. (2008) 5308-5314.

 

A. Le Chevalier-Isaad, A.M. Papini, M. Chorev,andP. Rovero. Side chain-to-side chain cyclization by click reaction. Peptide Protocol Paper. J. Pept. Sci.(2009), 15, 451-454.

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

M. Scrima, M. Grimaldi, S. Di Marino, C. Testa, P. Rovero, A.M. Papini, M. Chorev, and  A.M. D'Ursi. Solvent independent conformational propensities of [1,2,3]Triazolyl-bridged PTHrP-derived cyclo-nonapeptide analogues. Biopolymers: Peptide Science (2012) 98, 535–545. ISSN: 1097-0282, doi: 10.1002/bip.22139.

C. Testa, M. Scrima, M. Grimaldi, A.M. D’Ursi, M.L. Dirain, N. Lubin-Germain, A. Singh, C. Haskell-Luevano, M. Chorev, P. Rovero, A.M. Papini.1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: 2 Design, Synthesis, Conformational Analysis, and Biological Activity. J.Med.Chem. (2014) dx.doi.org/10.1021/jm501027w. Publication Date (Web): October 27, 2014.