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.