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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
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Identifiers
http://hdl.handle.net/10379/15210
 https://doi.org/10.13025/15105
Publication Date
2019-04-19
Keywords
Oxaliplatin, Pt(IV) prodrugs, Redox stress, Indole propionic acid, Cytotoxicity, PLATINUM(IV) COMPLEXES, CISPLATIN, CANCER, PRODRUG, DESIGN, AGENTS
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Citation
Tolan, Dina, Almotairy, Awatif Rashed Z., Howe, Orla, Devereux, Michael, Montagner, Diego, & Erxleben, Andrea. (2019). Cytotoxicity and ROS production of novel Pt(IV) oxaliplatin derivatives with indole propionic acid. Inorganica Chimica Acta, 492, 262-267. doi: https://doi.org/10.1016/j.ica.2019.04.038
Abstract
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.
Funder
Taibah University PhD scholarship
Egyptian Ministry of Higher Education (MoHE)
Publisher
Elsevier
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Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
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School of Biological and Chemical Sciences (Scholarly Articles)