Rhein to impart antimetastatic features to Pt(IV) complexes and to target brain

The combination of an anticancer Pt drug and another coadjutant molecule with different biological targets is a promising therapeutic strategy. Octahedral Pt(IV) complexes allow to combine cisplatin-like moieties and a second anticancer agent in a single molecule to obtain potential bifunctional antiproliferative prodrugs. Indeed, in the hypoxic and reducing tumor environment Pt(IV) complexes are activated by a two-electron reduction to form an active Pt(II) metabolite with concomitant loss of the second agent, when linked to the metal in axial position. The natural anthranoid rhein or cassic acid has several pharmacological effects and exerts anticancer effects by modulating cellular proliferation, apoptosis, migration, and invasion. Moreover, it can inhibit in vivo glioma tumor progression. For this reason, cisplatin-based Pt(IV) derivatives were synthesized by differently linking rhein to the metal. The complexes proved to be similar to or more potent than cisplatin and rhein, and temozolomide (reference drug) on glioblastoma cells. The Pt(IV) complexes caused a significant decrease in the motility of cells, which can be related to inhibition of matrix metalloproteinases.