Time filter

Source Type

Fernandez-Llamazares A.I.,Barcelona Institute for Research in Biomedicine | Fernandez-Llamazares A.I.,CIBER ISCIII | Adan J.,Leitat Technological Center Institution | Mitjans F.,Leitat Technological Center Institution | And 6 more authors.
Bioconjugate Chemistry | Year: 2014

Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed as a highly active and selective ligand for the α vβ3 and αvβ5 integrin receptors. We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide monomer units. The different N-OEG cyclopeptides and the original peptide were compared with respect to lipophilicity and biological activity. The N-OEG2 analogue was straightforward to synthesize in solid phase using an Fmoc-N-OEG2 building block. The syntheses of the N-OEG 11 and N-OEG23 cyclopeptides are hampered by the increased steric hindrance of the N-substituent, and could only be achieved by segment coupling, which takes place with epimerization and thus requires extensive product purification. All the N-OEG analogues were found to be more hydrophobic than the parent peptide, and their hydrophobicity was systematically enhanced upon increasing the length of the OEG chain. The N-OEG2 cyclopeptide displayed the same capacity as Cilengitide to inhibit the integrin-mediated adhesion of HUVEC endothelial, DAOY gliobastoma, and HT-29 colon cancer cells to their ligands vitronectin and fibrinogen. The N-OEG11 and N-OEG 23 analogues also inhibited cell adhesion to these immobilized ligands, but their IC50 values dropped by 1 order of magnitude with respect to the parent peptide. These results indicate that replacement of the backbone N-Me group of Cilengitide by a short N-OEG chain provides a more lipophilic analogue with a similar biological activity. Upon increasing the size of the N-OEG chain, liophilicity is enhanced, but synthetic yields drop and the longer polymer chains may impede targeted binding. © 2013 American Chemical Society.


Fernandez-Llamazares A.I.,Barcelona Institute for Research in Biomedicine | Fernandez-Llamazares A.I.,CIBER ISCIII | Fernandez-Llamazares A.I.,Leitat Technological Center Institution | Garcia J.,Barcelona Institute for Research in Biomedicine | And 10 more authors.
Organic Letters | Year: 2013

A robust synthetic strategy for the introduction of the N-(4-azidobutyl) linker into peptides using standard SPPS techniques is described. Based on the example of Cilengitide it is shown that the N-(4-azidobutyl) group exerts similar conformational restraints as a backbone N-Me group and allows conjugation of a desired molecule either via click chemistry or - after azide reduction - via acylation or reductive alkylation. © 2013 American Chemical Society.


Cupido T.,Barcelona Institute for Research in Biomedicine | Spengler J.,Barcelona Institute for Research in Biomedicine | Ruiz-Rodriguez J.,Barcelona Institute for Research in Biomedicine | Adan J.,Leitat Technological Center Institution | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2010

(Figure Presented) Without affecting the overall 3D structure, amide-to-ester backbone substitution (or ester scan) exerts a pronounced influence on the conformational equilibrium of the RCD cyclopeptide cilengitide and its derivatives (see figure; RGD = Arg-GlyAsp). The appropriate substitution, which stabilized the receptor-complementary conformations, improved the biological activity of this integrin antagonist. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Loading Leitat Technological Center Institution collaborators
Loading Leitat Technological Center Institution collaborators