New mono- and di-functionalized Pt(IV) complexes as promising anticancer prodrugs

Cisplatin and its derivatives are anticancer drugs currently used in therapy whose commonly accepted mechanism of action mainly consists in the binding to the DNA. However, despite their efficacy, they show several side effects. On the other hand, Pt(IV) complexes are kinetically more inert than the Pt(II) counterparts, and thus less toxic. These complexes act as prodrugs which can be activated inside the cancer cells through reduction, thus releasing the active Pt(II) drug and the two axial ligands. The Pt(II) species are responsible for the cytotoxicity but the introduction of bioactive axial ligands might further improve the pharmacological properties of these molecules. This project aims to the synthesis of new Pt(IV) complexes endowed with bioactive axial ligands which, thorough reduction directly on the tumor site, could release the active molecules in situ, thus limiting the diffused side effects related to traditional Pt compounds. In this frame, different bioactive molecules (such as α-tocopherol succinate, gemcitabine, indole-3-carbinol and doxycycline) have been taken into account for the functionalization of the axial position of these complexes, with the aim of exploring a wider range of biological activities. Moreover, in order to expand the arsenal of potential drugs, other metals (namely, Pd and As) have been explored. Finally, the biological activity of some of the resulting compounds has been evaluated.