title: Macrocyclization of Peptide Side Chains by the Ugi Reaction: Achieving Peptide Folding and Exocyclic N-Functionalization in One Shot.
abstract: The cyclization of peptide side chains has been traditionally used to either induce or stabilize secondary structures (β-strands, helices, reverse turns) in short peptide sequences. So far, classic peptide coupling, nucleophilic substitution, olefin metathesis, and click reactions have been the methods of choice to fold synthetic peptides by means of macrocyclization. This article describes the utilization of the Ugi reaction for the side chain-to-side chain and side chain-to-termini macrocyclization of peptides, thus enabling not only access to stable folded structures but also the incorporation of exocyclic functionalities as N-substituents. Analysis of the NMR-derived structures revealed the formation of helical turns, β-bulges, and α-turns in cyclic peptides cross-linked at i, i + 3 and i, i + 4 positions, proving the folding effect of the multicomponent Ugi macrocyclization. Molecular dynamics simulation provided further insights on the stability and molecular motion of the side chain cross-linked peptides.
authors.affiliation: †Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba.|‡Facultad de Ingeniería Química, Instituto Superior Politécnico José Antonio Echeverría, CUJAE, Calle 114 # 11901, 11500, La Habana, Cuba.
authors.forename: Aldrin V
authors.initials: AV
authors.lastname: Vasco
authors.affiliation: †Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Pérez
authors.affiliation: †Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba.
authors.forename: Fidel E
authors.initials: FE
authors.lastname: Morales
authors.affiliation: §Synthetic Peptides Group, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, La Habana, Cuba.
authors.forename: Hilda E
authors.initials: HE
authors.lastname: Garay
authors.affiliation: ⊥Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle/Saale, Germany.
authors.forename: Dimitar
authors.initials: D
authors.lastname: Vasilev
authors.affiliation: ∥Instituto Universitario de Bioorgánica Antonio González and Departamento de Química Orgánica, Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Gavín
authors.affiliation: ⊥Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle/Saale, Germany.
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
authors.affiliation: †Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Rivera
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D003500:Cyclization; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D010455:Peptides; D010456:Peptides, Cyclic