Cyclic isoDGR and RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds are Integrin Antagonists. Issue 16 (11th March 2015)

• Record Type: Journal Article
• Authors: Panzeri, Silvia; Zanella, Simone; Arosio, Daniela; Vahdati, Leila; Dal Corso, Alberto; Pignataro, Luca; Paolillo, Mayra; Schinelli, Sergio; Belvisi, Laura; Gennari, Cesare; Piarulli, Umberto
• Is Part Of: Chemistry. Volume 21:Issue 16(2015)
• Page Start: 6265
• Page End: 6271
• Publication Date: 2015-03-11
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201406567
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The <italic>cyclo</italic>[DKP‐<italic>iso</italic>DGR] peptidomimetics <bold>2</bold>–<bold>5</bold>, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified α_vβ₃ and α_vβ₅ integrin receptors. IC₅₀ values ranged from low nanomolar (ligand <bold>3</bold>) to submicromolar with α_vβ₃ integrin. The biological activities of ligands <italic>cyclo</italic>[DKP3‐RGD] <bold>1</bold> and <italic>cyclo</italic>[DKP3‐<italic>iso</italic>DGR] <bold>3</bold>, bearing the same bifunctional DKP scaffold and showing similar α_Vβ₃ integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds <bold>1</bold> and <bold>3</bold> displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin‐mediated cell infiltration processes, and qualify therefore, despite the different RGD and <italic>iso</italic>DGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.</p> </abstract>