title: Cyclic aza-peptide integrin ligand synthesis and biological activity.
abstract: Aza-peptides are obtained by replacement of the α-C-atom of one or more amino acids by a nitrogen atom in a peptide sequence. Introduction of aza-residues into peptide sequences may result in unique structural and pharmacological properties, such that aza-scanning may be used to probe structure-activity relationships. In this study, a general approach for the synthesis of cyclic aza-peptides was developed by modification of strategies for linear aza-peptide synthesis and applied in the preparation of cyclic aza-pentapeptides containing the RGD (Arg-Gly-Asp) sequence. Aza-amino acid scanning was performed on the cyclic RGD-peptide Cilengitide, cyclo[R-G-D-f-N(Me)V] 1, and its parent peptide cyclo(R-G-D-f-V) 2, potent antagonists of the αvβ3, αvβ5, and α5β1 integrin receptors, which play important roles in human tumor metastasis and tumor-induced angiogenesis. Although incorporation of the aza-residues resulted generally in a loss of binding affinity, cyclic aza-peptides containing aza-glycine retained nanomolar activity toward the αvβ3 receptor.
authors.affiliation: Department Chemie, Institute for Advanced Study, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Spiegel
authors.forename: Carlos
authors.initials: C
authors.lastname: Mas-Moruno
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000595:Amino Acid Sequence; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; C047981:arginyl-glycyl-aspartic acid