COMBINATION THERAPY THROUGH PLATINUM (IV) PRODRUG COMPLEXES INCORPORATING SELF-IMMOLATING LINKERS

Abstract

The discovery of the anticancer platinum complex cisplatin initiated research into the field of metallodrugs. However, the efficacy of cisplatin is hampered by low selectivity and severe side effects. In combination chemotherapy, drugs with different physical properties may also not be delivered synchronously. We investigated the conjugation of cisplatin to a synergistic drug using a self-immolating linker, aiming to create a Pt(IV) complex which releases both unaltered drugs concurrently. We have ascertained the previously-unstudied reduction behaviour of Pt(IV) carbamates, and developed new methodology to access them using the Curtius Rearrangement. Three self-immolating linkers were investigated for compatibility with cisplatin, and several complexes were synthesized as proof of concept. Combination therapy though drug synergy was also investigated by synthesizing a rationally-designed Pt(IV) prodrug which released cisplatin and a synergistic GST inhibitor upon activation. It was found to have comparable efficacy to cisplatin, but showed a significantly improved safety profile in vivo.