Expanding the Arsenal of PtIV Anticancer Agents: Multi‐action PtIV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group. (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. Volume 131:Number 50(2019)
• Page Start: 18386
• Page End: 18391
• Publication Date: 2019-10-28
• Subjects: Gemcitabin -- Platin -- Propharmaka -- Taxol -- Tumortherapeutika; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201910014
• Languages: English
• ISSNs: 0044-8249

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 : Axial angeknüpft : Die Konjugation eines Tumortherapeutikums mit der axialen Position von Pt IV in einem Cisplatin‐Propharmakon ermöglicht die Freisetzung des aktiven Wirkstoffs bei Reduktion von Pt IV in Krebszellen. Der axiale Hydroxidoligand von Pt IV und die Hydroxygruppe des Tumortherapeutikums wurden mithilfe eines Carbonats verbrückt. Das Gemcitabin‐Cisplatin‐Konjugat war potenter und ungiftiger als Gemcitabin allein oder gemeinsam verabreichtes Gemcitabin und Cisplatin.