Cyclopropane Pipecolic Acids as Templates for Linear and Cyclic Peptidomimetics: Application in the Synthesis of an Arg‐Gly‐Asp (RGD)‐Containing Peptide as an α v β 3 Integrin Ligand

• Published in: Chemistry : a European journal Vol. 20; no. 35; pp. 11187 - 11203
• Main Authors: Sernissi, Lorenzo, Petrović, Martina, Scarpi, Dina, Guarna, Antonio, Trabocchi, Andrea, Bianchini, Francesca, Occhiato, Ernesto G.
• Format: Journal Article
• Language: English
• Published: 25.08.2014
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201403077

Abstract The synthesis and evaluation of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for linear and cyclic peptidomimetics is reported. A variety of differently substituted (poly)hydroxy‐ and amino‐2‐azabicyclo[4.1.0]heptane‐1‐carboxylic acids were prepared by means of the Pd‐catalyzed methoxycarbonylation of suitably functionalized lactam‐derived enol phosphates, followed by OH‐directed cyclopropanation. CPAs were successfully introduced into a linear peptide sequence to assess the cis / trans isomerism about the pipecolic acid peptide bond, and in a cyclic peptidomimetic that bore the Arg‐Gly‐Asp (RGD) sequence, which displayed nanomolar activity as antagonist of the α v β 3 integrin in M21 human melanoma cells. Thus, CPAs appear to be suitable for the generation of novel peptidomimetics for drug discovery.