PDF(Pubmed)
Abstract：
Cancer cells generally present a higher demand for iron, which plays crucial roles in tumor progression and metastasis. This iron addiction provides opportunities to develop broad spectrum anticancer drugs that target iron metabolism. In this context, prochelation approaches are investigated to release metal-binding compounds under specific conditions, thereby limiting off-target toxicity. Here, we demonstrate a prochelation strategy inspired by the bioreduction of tetrazolium cations widely employed to assess the viability of mammalian cells. We designed a series of tetrazolium-based compounds for the intracellular release of metal-binding formazan ligands. The combination of reduction potentials appropriate for intracellular reduction and an N-pyridyl donor on the formazan scaffold led to two effective prochelators. The reduced formazans bind as tridentate ligands and stabilize low-spin Fe(II) centers in complexes of 2:1 ligand-to-metal stoichiometry. The tetrazolium salts are stable in blood serum for over 24 h, and antiproliferative activities at micromolar levels were recorded in a panel of cancer cell lines. Additional assays confirmed the intracellular activation of the prochelators and their ability to affect cell cycle progression, induce apoptotic death, and interfere with iron availability. Demonstrating the role of iron in their intracellular effects, the prochelators impacted the expression levels of key iron regulators (i.e., transferrin receptor 1 and ferritin), and iron supplementation mitigated their cytotoxicity. Overall, this work introduces the tetrazolium core as a platform to build prochelators that can be tuned for activation in the reducing environment of cancer cells and produce antiproliferative formazan chelators that interfere with cellular iron homeostasis.
摘要：
癌细胞通常对铁提出更高的需求，在肿瘤的进展和转移中起着至关重要的作用。这种铁成瘾为开发靶向铁代谢的广谱抗癌药物提供了机会。在这种情况下，研究了在特定条件下释放金属结合化合物的前螯合方法，从而限制脱靶毒性。这里,我们展示了一种受四唑阳离子生物还原启发的前螯合策略，广泛用于评估哺乳动物细胞的生存能力。我们设计了一系列基于四唑的化合物，用于细胞内释放金属结合甲配体。适合于细胞内还原的还原电位和甲支架上的N-吡啶基供体的组合导致两种有效的前螯合剂。还原的甲as作为三齿配体结合，并稳定2：1配体与金属化学计量的配合物中的低自旋Fe（II）中心。四唑盐在血清中稳定超过24小时，在一组癌细胞系中记录了微摩尔水平的抗增殖活性。其他试验证实了前螯合剂的细胞内激活及其影响细胞周期进程的能力。诱导凋亡性死亡，并干扰铁的供应。证明铁在其细胞内作用中的作用，前螯合剂影响关键铁调节剂的表达水平(即转铁蛋白受体1和铁蛋白），补充铁减轻了它们的细胞毒性。总的来说,这项工作介绍了四唑核作为一个平台，以建立前螯合剂，可以调节激活在还原环境的癌细胞，并产生抗增殖甲螯合剂，干扰细胞铁稳态。
