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Cytotoxicity and ROS production of novel Pt(IV) oxaliplatin derivatives with indole propionic acid
Tolan, Dina; Almotairy, Awatif Rashed Z.; Howe, Orla; Devereux, Michael; Montagner, Diego; Erxleben, Andrea
The coordination of biologically active moieties to the axial positions of Pt(IV) derivatives of Pt(II) anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV) complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV) complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by H-1 and Pt-195 NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)] (1), trans-[Pt(DACH)(ox)(IPA)(2)] (2), trans-[Pt(DACH)(ox)(IPA)(bz)] (3), trans-[Pt(DACH)(ox)(IPA)(suc)] (4), and trans-[Pt(DACH)(ox)(IPA)(ac)] (5) (DACH = 1,2-diaminocyclohexane (1R, 2R)-(-), ox = oxalate, IPA = indole 3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS) in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono-and bis-adducts [Pt(DACH)(guanosine)( OH)](+) and [Pt(DACH)(guanosine)(2)](2+) in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA. A.A. acknowledges a PhD scholarship from Taibah University. D.T. acknowledges the Egyptian Ministry of Higher Education (MoHE) for funding her re search stay at the National University of Ireland Galway. 2021-04-19
Keyword(s): Oxaliplatin; Pt(IV) prodrugs; Redox stress; Indole propionic acid; Cytotoxicity; PLATINUM(IV) COMPLEXES; CISPLATIN; CANCER; PRODRUG; DESIGN; AGENTS
Publication Date:
2019
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Contributor(s): Taibah University PhD scholarship; Egyptian Ministry of Higher Education (MoHE)
Institution: NUI Galway
Publisher(s): Elsevier
File Format(s): application/pdf
First Indexed: 2019-09-20 06:39:48 Last Updated: 2019-09-20 06:39:48