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 \u3b1 and \u3b2 transmembrane glycoproteins and are involved in important physiological and pathological processes.[1] Several integrins, including \u3b1V\u3b23, \u3b1V\u3b25, \u3b15\u3b21, and \u3b1IIb\u3b23, 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 \u3b1V\u3b23 and \u3b1V\u3b25 integrins has been studied.[3] One low-nanomolar ligand (IC50 = 9.2 \ub1 1.1 nM) was identified, namely cyclo[DKP3-isoDGR], which is, to the best of our knowledge, the most potent isoDGR \u3b1V\u3b23 integrin ligand reported so far. The biological activities of ligands cyclo[DKP3-RGD] and cyclo[DKP3-isoDGR], bearing the same bifunctional diketopiperazine (DKP) scaffold and showing similar \u3b1V\u3b23 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. This conjugate retained a low-nanomolar \u3b1V\u3b23 integrin binding value (IC50 = 11.0 \ub1 0.2 nM)