Synthesis, characterization, reactivity and biological evaluation of octahedral Pt(IV) prodrugs with active axial ligands

Platinum(II) complexes are very important drugs in anticancer chemotherapy. Although few Pt(II) complexes have been approved for the clinical use, in recent years attention has been paid to Pt(IV) complexes as prodrugs, which generally exhibit higher chemical inertness than their Pt(II) counterparts and undergo fewer side reactions with biomolecules. These complexes can be in vivo reduced in the hypoxic and reducing environment of the tumor so that the octahedral Pt(IV) complexes are transformed into their active square-planar Pt(II) metabolites by loss of the axial ligands (activation by reduction). The choice of the ligands is essential to modulate lipophilicity and redox properties of the Pt(IV) prodrugs: they can be biologically active molecules themselves (synthesizing, in this way, bifunctional prodrugs) or linker between the Pt core and a vector for drug targeting and delivery (DTD) methods. The works of this thesis is composed by three projects about three different topics of the modern research on platinum anticancer drug development. The first project involves the development of a new way for the oxidation of Pt(II) complexes with N-chlorosuccinimide as oxidant in ethylene glycol and the study of the stability and reactivity toward different reactions (esterification, synthesis of carbamates and CuAAC click chemistry reaction) of the resulting axially unsymmetric Pt(IV) complexes. The second project, inspired by the philosophy of the active drug targeting and delivery strategy, is aimed to evaluate the effect of the anchoring site of glutamine and glutamine-like to the platinum complex on the cellular recognition by means of antiproliferative activity and cellular uptake tests. The third project is focused on the bifunctional drug concept and is structured in the synthesis, characterization and evaluation of the antiproliferative activity of cisplatin- and [PtCl2(1R,2R-cyclohexanediamine)]- based Pt(IV) complexes bearing clofibric and perillic acid as bioactive axial ligands.