Cyclic RGD peptidomimetics containing 4-and 5-aminocyclopropane pipecolic acid (CPA) templates as dual alpha(V)beta(3) and alpha(5)beta(1) 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 di...

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Published inBioorganic & medicinal chemistry Vol. 24; no. 4; pp. 703 - 711
Main Authors Sernissi, Lorenzo, Trabocchi, Andrea, Scarpi, Dina, Bianchini, Francesca, Occhiato, Ernesto G.
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 15.02.2016
Subjects
Biochemistry & Molecular Biology
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
DESIGN
CRYSTAL-STRUCTURE
STRATEGIES
CILENGITIDE
Synthesis
2,3-Methanopipecolic acids
Peptidomimetics
STRUCTURAL BASIS
ALPHA-V-BETA-3
BIOLOGICAL EVALUATION
FIBRONECTIN
Ligands
SELECTIVITY
ALPHA-5-BETA-1 INTEGRIN
Integrins
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.12.039