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

Lorenzo Sernissi; Andrea Trabocchi; Dina Scarpi; Francesca Bianchini; Ernesto G Occhiato

doi:10.1016/j.bmc.2015.12.039

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

Bioorg Med Chem. 2016 Feb 15;24(4):703-11. doi: 10.1016/j.bmc.2015.12.039. Epub 2015 Dec 24.

Authors

Lorenzo Sernissi¹, Andrea Trabocchi¹, Dina Scarpi¹, Francesca Bianchini², Ernesto G Occhiato³

Affiliations

¹ Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
² Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, I-50134 Florence, Italy.
³ Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy. Electronic address: ernesto.occhiato@unifi.it.

PMID: 26753814
DOI: 10.1016/j.bmc.2015.12.039

Abstract

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=2.4nM) toward the αvβ3 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 α5β1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual αvβ3 and α5β1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy.

Keywords: 2,3-Methanopipecolic acids; Integrins; Ligands; Peptidomimetics; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Adhesion / drug effects
Cell Line, Tumor
Cyclopropanes / chemistry
Cyclopropanes / pharmacology*
Dose-Response Relationship, Drug
Humans
Integrin alphaVbeta3 / antagonists & inhibitors
Integrin alphaVbeta3 / metabolism*
K562 Cells
Ligands
Models, Molecular
Molecular Structure
Peptides, Cyclic / chemistry*
Peptidomimetics / chemical synthesis
Peptidomimetics / chemistry*
Peptidomimetics / pharmacology*
Pipecolic Acids / chemistry
Pipecolic Acids / pharmacology*
Receptors, Vitronectin / antagonists & inhibitors
Receptors, Vitronectin / metabolism*
Structure-Activity Relationship

Substances

Cyclopropanes
Integrin alphaVbeta3
Ligands
Peptides, Cyclic
Peptidomimetics
Pipecolic Acids
Receptors, Vitronectin
cyclic arginine-glycine-aspartic acid peptide
integrin alphavbeta1
cyclopropane