Angewandte Chemie - International Edition p. 18218 - 18223 (2019)
Update date:2022-08-10
Topics:
Yempala, Thirumal
Babu, Tomer
Karmakar, Subhendu
Nemirovski, Alina
Ishan, Maisaloon
Gandin, Valentina
Gibson, Dan
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 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 PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), 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], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine.
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