Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents

Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and cell growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes to induce ferroptosis. Iron depletion inhibits cell proliferation, while iron overload induces the damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading to genome instability. Here, we demonstrated that designing a molecular chimera embodying structural requirements for both iron chelation and G-quadruplex binding can result in dual-targeting compounds endowed with synergistic anticancer effects. We designed, synthesized, and tested a library of such compounds through biophysical and biological experiments. Compound 16 emerged as a lead candidate and a pharmacological tool able to chelate iron and stabilize G-quadruplexes in human leukemia Jurkat cells. Notably, it also localizes in the cell nucleus, serving as an intrinsically fluorescent nuclear tracer for the labile iron pool.

铁稳态（Iron homeostasis）与诸多生理通路紧密相关，涵盖细胞周期进程与细胞生长过程。最新的抗癌策略主要聚焦于两大方向：一是通过合适的螯合剂耗尽细胞内铁含量，二是通过给予铁配合物以提升细胞铁负荷，进而诱导铁死亡（ferroptosis）。铁耗竭会抑制细胞增殖，而铁过载则会通过活性氧（Reactive Oxygen Species, ROS）的产生，诱导G-四链体（G-quadruplex）结构中的鸟嘌呤核苷酸碱基受损，最终引发基因组不稳定。本研究证实，设计兼具铁螯合与G-四链体结合结构需求的分子嵌合体，可获得具备协同抗癌效应的双靶点化合物。我们通过生物物理与生物学实验，设计、合成并测试了该类化合物的化合物库。化合物16脱颖而出，成为先导候选化合物与药理学工具，可在人白血病Jurkat细胞中螯合铁离子并稳定G-四链体结构。值得注意的是，该化合物还可定位于细胞核，可作为不稳定铁池（labile iron pool）的内源性荧光核示踪剂。