title: Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains.
abstract: 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 We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide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.
authors: Institute for Research in Biomedicine (IRB) Barcelona, ‡CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, and ∥Biomed Division, Leitat Technological Center Institution, Barcelona Science Park , Baldiri Reixac 10, 08028 Barcelona, Spain.
authors: Ana I
authors: AI
authors: Fernández-Llamazares
authors: Jaume
authors: J
authors: Adan
authors: Francesc
authors: F
authors: Mitjans
authors: Jan
authors: J
authors: Spengler
authors: Fernando
authors: F
authors: Albericio
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008968:Molecular Conformation; D012910:Snake Venoms / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000378:metabolism
chemical_list: D005026:Ethylene Glycols; D016023:Integrins; D008024:Ligands; D012910:Snake Venoms; D019096:Vitronectin; C422910:Cilengitide; D005340:Fibrinogen