Expanding the Arsenal of PtIV Anticancer Agents: Multi‐action PtIV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group. Issue 50 (28th October 2019)

• Record Type: Journal Article
• Authors: Yempala, Thirumal; Babu, Tomer; Karmakar, Subhendu; Nemirovski, Alina; Ishan, Maisaloon; Gandin, Valentina; Gibson, Dan
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 50(2019)
• Page Start: 18218
• Page End: 18223
• Publication Date: 2019-10-28
• Subjects: anticancer -- gemcitabine -- platinum -- prodrug -- taxol; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201910014
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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 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. Abstract : The conjugation of an anticancer agent to the axial position of Pt IV in a cisplatin prodrug enables the release of the active drug upon reduction of Pt IV inside cancer cells. A carbonate was used to bridge the hydroxido axial ligand of Pt IV and the hydroxy group of the anticancer agent. The gemcitabine–cisplatin conjugate was more potent and less toxic than gemcitabine alone or co‐administered gemcitabine and cisplatin.