Expanding the Arsenal of Pt Anticancer Agents: Multi-action Pt Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group.

Most multi-action Pt 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 drug 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 Pt prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO , rapidly generating the active drugs. In contrast, succinate-linked drugs did not readily release the free drugs. The carbonate-bridged ctc-[Pt(NH ) (PhB)(Gem-Carb)Cl ] was significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH ) (PhB)(Gem-Suc)Cl ], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine.