Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress

Wang, Qin; Franz, Katherine J.

doi:10.1016/j.bmc.2018.11.004

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…The relative Fe(II) binding efficacy of formazans 2a and 4a was assessed in vitro using calcein, 41 a fluorescent probe that is commonly employed to monitor changes in the cytosolic labile iron pool (vide infra). 42 Calcein is mostly quenched when bound to Fe(II) (1.0 equiv, K d = 0.14 μM), 42 but fluorescence is restored when chelators displace iron from the probe.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Design of Tetrazolium Cations for the Release of Antiproliferative Formazan Chelators in Mammalian Cells

Sung

Tomat

2023

J. Am. Chem. Soc.

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Design of Tetrazolium Cations for the Release of Antiproliferative Formazan Chelators in Mammalian Cells

Sung

Tomat

2023

J. Am. Chem. Soc.

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“…78 Unfortunately, 44 failed to achieve full conversion to SIH under oxidative conditions because of its hydrolytic susceptibility in aqueous solutions causing conversion to its hydrolysis product isoniazid. 82 Several modifications to 44 improved its hydrolytic stability while maintaining low cytotoxicity, 83 including the second-generation prochelator 45 with increased hydrolytic stability in plasma. 84,85 Prochelator 45 did not induce iron deficiency in cultured retinal pigment epithelial cells and it showed cardioprotective effects against catecholamine-induced oxidative cellular injury.…”

Section: Prochelatorsmentioning

confidence: 99%