Cyclic isoDGR and RGD peptidomimetics: integrin antagonists and tumor-homing devices

Integrins are a large family of cell adhesion receptors composed of two non-covalently bound α and β transmembrane glycoproteins and are involved in physiological and pathological processes.[1] Several integrins, including αVβ3, αVβ5, α5β1, and αIIbβ3, recognize endogenous ligands using the tripeptide sequence Arg-Gly-Asp (RGD) and its mimic isoAsp-Gly-Arg (isoDGR).[2] Four cyclo[DKP-isoDGR] integrin ligands have been synthesized and their ability to bind αVβ3 and αVβ5 integrins has been studied.[3] At least one low-nanomolar ligand was identified, namely cyclo[DKP3-isoDGR], which is, to the best of our knowledge, the most potent isoDGR αVβ3 integrin ligand reported so far (Figure 1). The biological activities of ligands cyclo[DKP3-RGD] and cyclo[DKP3-isoDGR], bearing the same bifunctional diketopiperazine (DKP) scaffold and showing similar αVβ3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. They displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin mediated cell infiltration processes, and qualify therefore as integrin antagonists. With the aim of exploiting the tumor-homing potential[4] of cyclo[DKP3-isoDGR], a cyclic isoDGR peptidomimetic displaying a proper handle for conjugation to cytotoxic agents has been developed.