Expanding the Arsenal of PtIV Anticancer Agents; Multi-action PtIV Anticancer Agents with Bioactive Ligands Possessing Hydroxyl Functional Group.

Abstract

Most multi-action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active form of the agent is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV prodrugs that release in their native form, molecules with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel, and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active drugs. In contrast, succinate linked drugs did not readily release the free drugs. The carbonate bridged ctc-[Pt(NH3)2(PhB)(Gem-Carb)Cl2] was significantly more cytotoxic than the succinate bridged ctc-[Pt(NH3)2(PhB)(Gem-Suc)Cl2]. In vivo data show that carbonate-bridged compound was more potent and less toxic than gemcitabine, cisplatin and co-administration pf cisplatin and gemcitabine.