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Expanding the Arsenal of Pt IV Anticancer Agents: Multi‐action Pt IV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group
Author(s) -
Yempala Thirumal,
Babu Tomer,
Karmakar Subhendu,
Nemirovski Alina,
Ishan Maisaloon,
Gandin Valentina,
Gibson Dan
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201910014
Subject(s) - prodrug , chemistry , cisplatin , gemcitabine , stereochemistry , paclitaxel , combinatorial chemistry , carboxylate , medicinal chemistry , chemotherapy , biochemistry , medicine , surgery
Most multi‐action Pt IV 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 IV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt IV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO 2 , rapidly generating the active drugs. In contrast, succinate‐linked drugs did not readily release the free drugs. The carbonate‐bridged ctc ‐[Pt(NH 3 ) 2 (PhB)(Gem‐Carb)Cl 2 ] was significantly more cytotoxic than the succinate‐bridged ctc ‐[Pt(NH 3 ) 2 (PhB)(Gem‐Suc)Cl 2 ], and more potent and less toxic than gemcitabine, cisplatin, and co‐administration of cisplatin and gemcitabine.