Tackling Lipophilicity of Peptide Drugs: Replacement of the Backbone N-Methyl Group of Cilengitide by N-Oligoethylene Glycol (N-OEG) Chains
| Autor: | Jaume Adan, Fernando Albericio, Ana I. Fernández-Llamazares, Jan Spengler, Francesc Mitjans |
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| Rok vydání: | 2013 |
| Předmět: |
Steric effects
Integrins Stereochemistry Molecular Conformation Biomedical Engineering Pharmaceutical Science Bioengineering Peptide Cilengitide Ligands Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Cell Adhesion Human Umbilical Vein Endothelial Cells Humans Structure–activity relationship Vitronectin Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Ligand Organic Chemistry Fibrinogen Monomer chemistry Lipophilicity Ethylene Glycols HT29 Cells Hydrophobic and Hydrophilic Interactions Snake Venoms Biotechnology Methyl group |
| Zdroj: | Bioconjugate Chemistry. 25:11-17 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc4003844 |
| Popis: | 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 We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide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. |
| Databáze: | OpenAIRE |
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