新型去铁胺化合物可有效螯合过量铁以治疗铁过载障碍并预防铁死亡,Advanced Science

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新型去铁胺化合物可有效螯合过量铁以治疗铁过载障碍并预防铁死亡
Advanced Science ( IF 14.3 ) Pub Date : 2022-08-28 , DOI: 10.1002/advs.202202679
Wenya Feng _{1,

2} , Yuanjing Xiao ₃ , Chuanfang Zhao _{1,

2} , Zhanming Zhang ₄ , Wei Liu _{1,

2} , Juan Ma _{1,

2} , Tomas Ganz ₅ , Junliang Zhang ₄ , Sijin Liu _{1,

2}

Affiliation

患有某些遗传疾病或反复输血后的患者器官会出现过量的铁积累。没有生理机制可用于排泄过量的铁和铁过载以促进脂质过氧化以诱导铁死亡，因此铁螯合对于预防这些患者的离子毒性至关重要。迄今为止，几种铁螯合剂已被批准用于铁螯合疗法，例如去铁酮和去铁胺，但目前的铁螯合剂存在明显的局限性。在此背景下，不断寻求新的代理。在这里，通过采用传统螯合剂的有益特性，合成了具有可调节骨架和柔韧性的新型去铁胺化合物 ( DFA ) 库。经过仔细评估，化合物DFA1发现通过酚羟基中的两个分子氧和胺中的氮原子以 2:1 的化学计量结合铁具有更大的功效。该化合物通过口服和静脉给药显着改善多种小鼠模型中的铁过载，包括血色素沉着症、高铁饮食诱导的铁和右旋糖酐刺激的铁积累。引人注目的是，该化合物被发现可以通过调节驱动脂质过氧化的细胞内信号来抑制铁诱导的铁死亡。该研究为开发治疗铁过载的铁螯合剂开辟了一条新途径。

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New Deferric Amine Compounds Efficiently Chelate Excess Iron to Treat Iron Overload Disorders and to Prevent Ferroptosis

Excess iron accumulation occurs in organs of patients with certain genetic disorders or after repeated transfusions. No physiological mechanism is available to excrete excess iron and iron overload to promote lipid peroxidation to induce ferroptosis, thus iron chelation becomes critical for preventing ion toxicity in these patients. To date, several iron chelators have been approved for iron chelation therapy, such as deferiprone and deferoxamine, but the current iron chelators suffer from significant limitations. In this context, new agents are continuously sought. Here, a library of new deferric amine compounds (DFAs) with adjustable skeleton and flexibility is synthesized by adopting the beneficial properties of conventional chelators. After careful evaluations, compound DFA1 is found to have greater efficacy in binding iron through two molecular oxygens in the phenolic hydroxyl group and the nitrogen atom in the amine with a 2:1 stoichiometry. This compound remarkably ameliorates iron overload in diverse murine models through both oral and intravenous administration, including hemochromatosis, high iron diet-induced, and iron dextran-stimulated iron accumulation. Strikingly, this compound is found to suppress iron-induced ferroptosis by modulating the intracellular signaling that drives lipid peroxidation. This study opens a new approach for the development of iron chelators to treat iron overload.

更新日期：2022-08-28

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