title: Cyclic RGD peptidomimetics containing 4- and 5-amino-cyclopropane pipecolic acid (CPA) templates as dual αVβ3 and α5β1 integrin ligands.
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.
authors.affiliation: Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sernissi
authors.affiliation: Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
authors.affiliation: Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Dina
authors.initials: D
authors.lastname: Scarpi
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, I-50134 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.affiliation: Department of Chemistry 'U. Schiff', University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy. Electronic address: ernesto.occhiato@unifi.it.
authors.forename: Ernesto G
authors.initials: EG
authors.lastname: Occhiato
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020014:K562 Cells; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000737:chemistry / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D039302:Integrin alphaVbeta3; D008024:Ligands; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D010875:Pipecolic Acids; D019030:Receptors, Vitronectin; C507169:cyclic arginine-glycine-aspartic acid peptide; C094340:integrin alphavbeta1; C030797:cyclopropane
keywords: 2,3-Methanopipecolic acids; Integrins; Ligands; Peptidomimetics; Synthesis