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重要组成部分。因此，它在体内的调节受到严格控制。体内铁水平的失调可导致与铁过多相关的几种疾病，包括血色素沉着症和地中海贫血，或缺铁。在体内铁过量的情况下，治疗包括通过静脉切开术（通常用于血色素沉着症）或使用铁螯合剂来治疗地中海贫血来消耗体内铁水平。然而，目前铁过载患者的螯合选择有限，只有三种铁螯合剂获准用于临床。这为识别和开发改进的治疗方法提供了机会。本研究的目的是检查戴维斯开放获取基于天然产物的库（512 种化合物）中的多种化合物螯合铁的能力。该文库的计算机分析初步确定了九种含儿茶酚的化合物和两种密切相关的化合物。随后使用体外 DNA 断裂试验筛选了这些化合物，并且还在载铁肝细胞试验中检查了它们螯合生物铁的能力。在肝细胞和乳腺癌细胞系中评估毒性。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，可能是通过防止芬顿反应产生的自由基；RAD362 处理导致载铁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。这是第一项将化合物 RAD362 鉴定为铁螯合剂和潜在治疗剂的研究。