Cyclic RGD peptidomimetics containing 4-and 5-aminocyclopropane pipecolic acid (CPA) templates as dual αVβ3 and α5β1 integrin ligands

4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50 = 2.4 nM) toward the alpha(V)beta(3) integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the alpha(5)beta(1) integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual alpha(V)beta(3) and alpha(5)beta(1) ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy. (c) 2015 Elsevier Ltd. All rights reserved.