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Altered redox status including higher levels of copper in cancer cells than in normal cells inspired many researchers to develop copper ionophores targeting this status. We have recently found that flavon-3-ol (3-HF) works as a potent Cu(II) ionophore by virtue of its keto-enol moiety. To further emphasize the significance of this moiety for developing Cu(II) ionophores, we herein designed a β-diketo analog of piperlongumine, PL-I, characterized by the presence of high proportion of the keto-enol form in dimethylsulfoxide and chloroform, and identified its keto-enol structure by NMR and theoretical calculations. Benefiting from deprotonation of its enolic hydroxyl group, this molecule is capable of facilitating the transport of Cu(II) through cellular membranes to disrupt redox homeostasis of human hepatoma HepG2 cells and trigger their death., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A main biochemical property of cancer cells, compared with normal cells, is altered redox status including increased levels of copper to maintain their malignant phenotypes. Thus, increasing copper accumulation, by using ionophores, to disrupt abnormal redox homeostasis of cancer cells may be an important anticancer strategy. Naturally occurring molecules with extraordinarily diverse chemical scaffolds are an important source of inspiration for developing copper ionophores. Dietary flavonoids are well-characterized copper chelators and show cancer chemopreventive potential, but their ionophoric role for redox-active copper and the related biological implications have remained unknown. This study reports, for the first time, the structural basis, chemical driving forces and biological implications of flavones (a widely distributed subgroup of flavonoids) as Cu(II) ionophores, and also provides new insights into cancer chemopreventive mechanism of flavones bearing 3(or 5)-hydroxy-4-keto group. 3-Hydroxyflavone surfaced as a potent Cu(II) ionophore to induce the mitochondria-dependent apoptosis of cancer cells in a redox intervention fashion via sequential proton-loss Cu(II) chelation, GSH-driving releasing of copper and protonation-dependent efflux of the neutral ligand., (Copyright © 2017 Elsevier Inc. All rights reserved.)