A Pt(IV) prodrug of kiteplatin with the bone-targeting pyrophosphate ligand

Abstract In this paper we report the synthesis and characterization of the complex c,t,c -[Pt(dihydrogen pyrophosphate)(OH) 2 ( cis -1,4-DACH)] ( 2 ), a Pt(IV) derivative of kiteplatin, which could be characterized by high bone tropism (due to the pyrophosphate ligand), enough stability to be administered orally, and activatable at the tumor site where the strong reduction conditions can promote its reduction to the corresponding Pt(II) counterpart with known cytotoxic activity. The new complex was characterized by ESI-MS, multinuclear NMR, X-Ray photoemission spectroscopy (XPS), and cyclic voltammetry (CV). 2 is very soluble in aqueous environment, very stable at physiological pH and quite stable also in acidic conditions (such as that of the stomach) with the possibility of oral administration. The in vitro cytotoxicity assays, performed against a panel of four human cancer cell lines, have shown that complex 2 has a cytotoxic activity comparable to that of cisplatin and slightly lower than that of kiteplatin and the pyrophosphate Pt(II) precursor. This behavior can be attributed to its reduced ability to enter cancer cells. However, the cytotoxic activity of 2 is very promising considering that generally Pt(IV) complexes have IC 50 values greater than those of the Pt(II) counterparts.