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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
Author(s) -
Sernissi Lorenzo,
Petrović Martina,
Scarpi Dina,
Guarna Antonio,
Trabocchi Andrea,
Bianchini Francesca,
Occhiato Ernesto G.
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201403077
Subject(s) - peptidomimetic , pipecolic acid , cyclopropane , stereochemistry , chemistry , peptide , cyclopropanation , amino acid , ligand (biochemistry) , combinatorial chemistry , catalysis , ring (chemistry) , receptor , organic chemistry , biochemistry
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.