The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol₃:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure–function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

天然产物桧酚可在低浓度下动员铁穿过脂质双层，并恢复铁转运蛋白缺乏系统中的血红蛋白化。但扁柏酚同样无法在较高浓度下动员铁，限制了其在化学生物学和医学中的应用。在这里，我们发现，在较高浓度下，扁柏酚₃ :Fe(III) 复合物形成大的、高阶聚集体，导致跨膜铁动员的损失。在这种理解和通过模块化合成实现的系统结构-功能研究的指导下，我们鉴定了 FeM-1269，即使在非常高的浓度下，它也能最小程度地聚集并剂量依赖性地跨脂质双层移动铁。与扁柏酚相比，FeM-1269 在动物体内长时间高剂量时也具有良好的耐受性。在炎症性贫血小鼠模型中，FeM-1269 增加血清铁、转铁蛋白饱和度、血红蛋白和血细胞比容。这种合理开发的铁动员小分子具有增强作为分子假体的潜力，用于理解和潜在治疗铁转运蛋白缺陷。