Cyclic isoDGR peptidomimetics: biological evaluation as integrin antagonists and synthesis of tumor-homing conjugates

Integrins are a large family of cell adhesion receptors composed of two non-covalently bound α and β transmembrane glycoproteins and are involved in important 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 (IC50 = 9.2 ± 1.1 nM) 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.[3] With the aim of exploiting the tumor-homing potential,[4] a cyclic isoDGR peptidomimetic displaying a proper handle for conjugation, cyclo[DKPf3-isoDGR], was synthesized and attached to Paclitaxel using a lysosomally cleavable linker (Figure 1). This conjugate retained a low-nanomolar αVβ3 integrin binding value (IC50 = 11.0 ± 0.2 nM).