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Rhein to impart antimetastatic features to Pt(IV) complexes and to target brain
* 1 , 2 , 3 , 3 , 4
1  Università del Piemonte Orientale, Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Piazza Sant'Eusebio 5, 13100 Vercelli, Italy
2  Università dell’Insubria, Dipartimento di Biotecnologie e Scienze della Vita (DBSV), via Dunant 3, Varese, Italy
3  Università di Torino, CASSMedChem, Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Via Quarello 15, 10135 Torino, Italy
4  Università del Piemonte Orientale, Dipartimento di Scienze e Innovazione Tecnologica, Viale Michel 11, 15121 Alessandria, Italy
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

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.

Keywords: antiproliferative activity; brain cancer; Pt(IV) complexes; rhein