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 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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Abbreviations
- ROS:
-
Reactive oxygen species
- FeSO4:
-
Ferrous sulphate
- FeCl3:
-
Ferric chloride
- H2O2 :
-
Hydrogen peroxide
- DF:
-
Deferoxamine mesylate
- FAC:
-
Ferric ammonium citrate
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Acknowledgements
The authors acknowledge the NatureBank biota repository (https://www.griffith.edu.au/institute-drug-discovery/unique-resources/naturebank) from which most of the Davis open access library compounds have been purified.
Funding
This work was supported in part by Project Grants from the National Health and Medical Research Council (NHMRC) of Australia (APP1029574 and APP1100088 to VNS; APP1024314 to RAD). VNS is the recipient of a NHMRC Senior Research Fellowship (APP1118888). The authors thank the Australian Research Council (ARC) for support toward NMR and MS equipment (Grants LE0668477, LE140100119 and LE0237908) and financial support (Grant LP120200339 to RAD). The funding sources have no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.
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Hawula, Z.J., Davis, R.A., Wallace, D.F. et al. In vitro identification and characterisation of iron chelating catechol-containing natural products and derivatives. Biometals 34, 855–866 (2021). https://doi.org/10.1007/s10534-021-00312-1
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DOI: https://doi.org/10.1007/s10534-021-00312-1