title: Searching for new cell-penetrating agents: hybrid cyclobutane-proline γ,γ-peptides.
abstract: Two generations of hybrid γ,γ-peptides containing cyclobutane amino acids and cis-γ-amino-L-proline joined in alternation have been synthesized and their capacity to cross the eukaryotic cell membrane has been evaluated. The first generation consists of di-, tetra- and hexapeptides, and their properties have been analyzed as well as the influence of peptide length and chirality of the cyclobutane residues. Results have shown that the absolute configuration of the cyclobutane amino acid does not have a relevant influence. The second generation consists of hybrid γ,γ-hexapeptides with a common backbone and distinct side chains introduced with different linkage types through the α-amino group (N(α)) of the proline monomers. These peptides have been shown to be non-toxic towards HeLa cells and to internalize them effectively, the best results being obtained for the peptides with a spacer of five carbons between the N(α) atom and the guanidinium group. The introduction of cyclobutane residues inside the sequence affords a good balance between charge and hydrophobicity, reducing the number of positive charges. This results in lower toxicity and similar cell-uptake properties when compared to previously described peptide agents.
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gorrea
authors.forename: Daniel
authors.initials: D
authors.lastname: Carbajo
authors.forename: Raquel
authors.initials: R
authors.lastname: Gutiérrez-Abad
authors.forename: Ona
authors.initials: O
authors.lastname: Illa
authors.forename: Vicenç
authors.initials: V
authors.lastname: Branchadell
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Ortuño
mesh_terms: D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D003503:Cyclobutanes / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011392:Proline / Q000737:chemistry
chemical_list: D003503:Cyclobutanes; D010455:Peptides; D011392:Proline