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  • In vitro identification and characterisation of iron chelating catechol-containing natural products and derivatives

    Author(s)
    Hawula, Zachary J
    Davis, Rohan A
    Wallace, Daniel F
    Rishi, Gautam
    Subramaniam, V Nathan
    Griffith University Author(s)
    Davis, Rohan A.
    Year published
    2021
    Metadata
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    Abstract
    Iron is an essential component for multiple biological processes. Its regulation within the body is thus tightly controlled. Dysregulation of iron levels within the body can result in several disorders associated with either excess iron accumulation, including haemochromatosis and thalassaemia, or iron deficiency. In cases of excess body iron, therapy involves depleting body iron levels either by venesection, typically for haemochromatosis, or using iron chelators for thalassemia. However, the current chelation options for people with iron overload are limited, with only three iron chelators approved for clinical use. This ...
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    Iron is an essential component for multiple biological processes. Its regulation within the body is thus tightly controlled. Dysregulation of iron levels within the body can result in several disorders associated with either excess iron accumulation, including haemochromatosis and thalassaemia, or iron deficiency. In cases of excess body iron, therapy involves depleting body iron levels either by venesection, typically for haemochromatosis, or using iron chelators for thalassemia. However, the current chelation options for people with iron overload are limited, with only three iron chelators approved for clinical use. This presents an opportunity for improved therapeutics to be identified and developed. The aim of this study was to examine multiple compounds from within the Davis open access natural product-based library (512 compounds) for their ability to chelate iron. In silico analysis of this library initially identified nine catechol-containing compounds and two closely related compounds. These compounds were subsequently screened using an in vitro DNA breakage assay and their ability to chelate biological iron was also examined in an iron-loaded hepatocyte cellular assay. Toxicity was assessed in hepatocyte and breast cancer cell lines. One compound, RAD362 [N-(3-aminopropyl)-3,4-dihydroxybenzamide] was able to protect against DNA damage, likely through the prevention of free radicals generated via the Fenton reaction; RAD362 treatment resulted in decreased ferritin protein levels in iron-loaded hepatocytes. Lastly, RAD362 resulted in significantly less cell death than the commonly used iron chelator deferoxamine. This is the first study to identify compound RAD362 as an iron chelator and potential therapeutic.
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    Journal Title
    BioMetals
    DOI
    https://doi.org/10.1007/s10534-021-00312-1
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Biochemistry and cell biology
    Science & Technology
    Life Sciences & Biomedicine
    Iron chelation
    Fenton reaction
    Molecular Biology
    Publication URI
    http://hdl.handle.net/10072/404566
    Collection
    • Journal articles

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