- Multifunctional Pt(iv) prodrug candidates featuring the carboplatin core and deferoxamine
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The synergistic combination of the anticancer drug carboplatin and the iron chelator deferoxamine (DFO) served as a foundation for the development of novel multifunctional prodrugs. Hence, five platinum(iv) complexes, featuring the equatorial coordination sphere of carboplatin, and one or two DFO units incorporated at axial positions, were synthesized and characterized using ESI-HRMS, multinuclear (1H,13C,15N,195Pt) NMR spectroscopy and elemental analysis. Analytical studies demonstrated that the chelating properties of the DFO moiety were not compromised after coupling to the platinum(iv) core. The cytotoxic activity of the compounds was evaluated in monolayer (2D) and spheroid (3D) cancer cell models, derived from ovarian teratocarcinoma (CH1/PA-1), colon carcinoma (SW480) and non-small cell lung cancer (A549). The platinum(iv)-DFO prodrugs demonstrated moderatein vitrocytotoxicity (a consequence of their slow activation kinetics) but with less pronounced differences between intrinsically chemoresistant and chemosensitive cell lines as well as between 2D and 3D models than the clinically used platinum(ii) drug carboplatin.
- Dyson, Paul J.,Enyedy, éva A.,Galanski, Mathea S.,Harringer, Sophia,Hejl, Michaela,Jakupec, Michael A.,Keppler, Bernhard K.,Varbanov, Hristo P.
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- The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity
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Iron-salen, i.e., μ-oxo-N,N′-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.
- Umemura, Masanari,Kim, Jeong-Hwan,Aoyama, Haruki,Hoshino, Yujiro,Fukumura, Hidenobu,Nakakaji, Rina,Sato, Itaru,Ohtake, Makoto,Akimoto, Taisuke,Narikawa, Masatoshi,Tanaka, Ryo,Fujita, Takayuki,Yokoyama, Utako,Taguri, Masataka,Okumura, Satoshi,Sato, Motohiko,Eguchi, Haruki,Ishikawa, Yoshihiro
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- ThIV-Desferrioxamine: Characterization of a fluorescent bacterial probe
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Diversifying our ability to guard against emerging pathogenic threats is essential for keeping pace with global health challenges, including those presented by drug-resistant bacteria. Some modern diagnostic and therapeutic innovations to address this challenge focus on targeting methods that exploit bacterial nutrient sequestration pathways, such as the desferrioxamine (DFO) siderophore used by Staphylococcus aureus (S. aureus) to sequester FeIII. Building on recent studies that have shown DFO to be a versatile vehicle for chemical delivery, we show proof-of-principle that the FeIII sequestration pathway can be used to deliver a potential radiotherapeutic. Our approach replaces the FeIII nutrient sequestered by H4DFO+ with ThIV and made use of a common fluorophore, FITC, which we covalently bonded to DFO to provide a combinatorial probe for simultaneous chelation paired with imaging and spectroscopy, H3DFO_FITC. Combining insight provided from FITC-based imaging with characterization by NMR spectroscopy, we demonstrated that the fluorescent DFO_FITC conjugate retained the ThIV chelation properties of native H4DFO+. Fluorescence microscopy with both [Th(DFO_FITC)] and [Fe(DFO_FITC)] complexes showed similar uptake by S. aureus and increased intercellular accumulation as compared to the FITC and unchelated H3DFO_FITC controls. Collectively, these results demonstrate the potential for the newly developed H3DFO_FITC conjugate to be used as a targeting vector and bacterial imaging probe for S. aureus. The results presented within provide a framework to expand H4DFO+ and H3DFO_FITC to relevant radiotherapeutics (like 227Th).
- Abergel, Rebecca J.,Aldrich, Kelly Elise,Janicke, Michael Timothy,Kozimor, Stosh Anthony,Lilley, Laura Margaret,Livshits, Maksim Yuryevich,Mukundan, Harshini,Nhu Lam, Mila,Stein, Benjamin,Stromberg, Loreen Rose,Wagner, Gregory Lawerence
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p. 15310 - 15320
(2021/11/17)
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- Iron Uptake Oxidoreductase (IruO) Uses a Flavin Adenine Dinucleotide Semiquinone Intermediate for Iron-Siderophore Reduction
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Many pathogenic bacteria including Staphylococcus aureus use iron-chelating siderophores to acquire iron. Iron uptake oxidoreductase (IruO), a flavin adenine dinucleotide (FAD)-containing nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase from S. aureus, functions as a reductase for IsdG and IsdI, two paralogous heme degrading enzymes. Also, the gene encoding for IruO was shown to be required for growth of S. aureus on hydroxamate siderophores as a sole iron source. Here, we show that IruO binds the hydroxamate-type siderophores desferrioxamine B and ferrichrome A with low micromolar affinity and in the presence of NADPH, Fe(II) was released. Steady-state kinetics of Fe(II) release provides kcat/Km values in the range of 600 to 7000 M-1 s-1 for these siderophores supporting a role for IruO as a siderophore reductase in iron utilization. Crystal structures of IruO were solved in two distinct conformational states mediated by the formation of an intramolecular disulfide bond. A putative siderophore binding site was identified adjacent to the FAD cofactor. This site is partly occluded in the oxidized IruO structure consistent with this form being less active than reduced IruO. This reduction in activity could have a physiological role to limit iron release under oxidative stress conditions. Visible spectroscopy of anaerobically reduced IruO showed that the reaction proceeds by a single electron transfer mechanism through an FAD semiquinone intermediate. From the data, a model for single electron siderophore reduction by IruO using NADPH is described.
- Kobylarz, Marek J.,Heieis, Graham A.,Loutet, Slade A.,Murphy, Michael E. P.
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p. 1778 - 1786
(2017/07/26)
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- Effect of pressure on the complex formation and aquation kinetics of iron (III) with hydroxamic acids
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The activation and reaction volumes for the formation and aquation of (acethydroxamato)iron(III) complexes, as well as the activation volumes for the formation of the (desferrioxamine B)iron(III) complex, have been obtained by high-pressure stopped-flow and UV-vis spectral measurements. The data indicate a gradual mechanistic changeover from Ia to Id for the stepwise proton-catalyzed hydrolysis of the tris(acethydroxamato)iron(III) complex and vice versa for the corresponding formation reactions. The activation volumes for the complexation of Fe(H2O)63+ and Fe(H2O)5(OH)2+ with both acethydroxamic acid (HA) and desferrioxamine B in its fully protonated form (H4dfb+) exhibit opposite signs, indicating associative and dissociative modes of activation, respectively. The obtained results suggest that the substitution behavior of the Fe(III) complexes is controlled by the presence of OH- or A- in the coordination sphere.
- Biru?, Mladen,Van Eldik, Rudi
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p. 4559 - 4563
(2008/10/08)
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