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.