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.
Aleman, C.; Jimenez, A.; Cativiela, C.; Nussinov, R.; Casanovas Salas, Jordi Journal of organic chemistry Vol. 74, num. 20, p. 7834-7843 DOI: 10.1021/jo901594e Data de publicació: 2009-10 Article en revista
The intrinsic conformational preferences of the restricted phenylalanine analogue generated by including the R and β carbon atoms into a cyclohexane ring (1-amino-2-phenylcyclohexanecarboxylic acid, c6Phe) have been determined using quantum mechanical calculations. Specifically, the
conformational profile of the N-acetyl-N0-methylamide derivative of the c6Phe stereoisomers exhibiting either a cis or a trans relative orientation between the amino and phenyl substituents has been analyzed in different environments (gas phase, chloroform, and aqueous solutions).
Calculations were performed using B3LYP, MP2, and HF methods combined with the 6-31+
G(d,p) and 6-311++G(d,p) basis sets, and a self-consistent reaction-field (SCRF) method was applied to analyze the influence of the solvent. The amino acids investigated can be viewed as constrained phenylalanine analogues with a rigidly oriented aromatic side chain that may interact with the peptide backbone not only sterically but also electronically through the aromatic π orbitals.
Their conformational propensities have been found to be strongly influenced by the specific orientation of the aromatic substituent in each stereoisomer and the conformation adopted by the cyclohexane ring, as well as by the environment.
Flores-Ortega, A.; Jimenez, A.; Cativiela, C.; Nussinov, R.; Aleman, C.; Casanovas Salas, Jordi Journal of organic chemistry Vol. 73, num. 9, p. 3418-3427 Data de publicació: 2008-05 Article en revista
Carilla, J.; Fajarí, Ll.; Garcia, R.; Julia, L.; Marcos, C.; Riera, J.; Whitaker, C.; Aleman, C. Journal of organic chemistry Vol. 60, num. 6, p. 2721-2725 Data de publicació: 1995-03 Article en revista