Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed 
as a highly active and selective ligand for the αvβ3 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the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of 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-OEG11 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-OEG23 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.