Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Avenue, Kelvin Grove, Brisbane, QLD, 4059, Australia.
Griffith Institute for Drug Discovery, Environment and Science, Griffith University, Brisbane, QLD, Australia.
Biometals. 2021 Aug;34(4):855-866. doi: 10.1007/s10534-021-00312-1. Epub 2021 Apr 28.
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.
铁是多种生物过程的必需组成部分。因此，体内的铁调节受到严格控制。体内铁水平的失调可能导致与铁过量积累相关的几种疾病，包括血色病和地中海贫血，或铁缺乏症。在体内铁过量的情况下，治疗方法包括通过静脉切开术（通常用于血色病）或使用铁螯合剂（用于地中海贫血）来消耗体内铁水平。然而，目前用于铁过载患者的螯合疗法有限，只有三种铁螯合剂被批准用于临床使用。这为发现和开发改进的治疗方法提供了机会。本研究的目的是研究戴维斯开放获取天然产物库（512 种化合物）中的多种化合物，以评估它们螯合铁的能力。该库的计算机分析最初确定了 9 种含有儿茶酚的化合物和 2 种密切相关的化合物。随后，使用体外 DNA 断裂测定法筛选这些化合物，并在负载铁的肝细胞测定法中检查它们螯合生物铁的能力。在肝细胞和乳腺癌细胞系中评估了毒性。一种化合物 RAD362[ N-（3-氨基丙基）-3,4-二羟基苯甲酰胺]能够防止 DNA 损伤，可能是通过防止 Fenton 反应产生的自由基；RAD362 处理导致负载铁的肝细胞中铁蛋白水平降低。最后，RAD362 导致的细胞死亡明显少于常用的铁螯合剂去铁胺。这是首次鉴定化合物 RAD362 为铁螯合剂和潜在治疗剂的研究。
