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Targeting redox vulnerability of cancer cells by pro-oxidants capable of generating reactive oxygen species (ROS) has surfaced as an important anticancer strategy. Due to the intrinsic narrow therapeutic window and other dangerous side effects of ROS generation, it is highly needed and challenging to develop pro-oxidative anticancer agents (PAAs) with high selectivity for generating ROS in cancer cells. Herein we report a hydrogen peroxide (H 2 O 2)-activated Cu(II) pro-ionophore strategy to develop naphthazarin (Nap) as such type of PAAs based on the H 2 O 2 -mediated conversion of boronate to free phenol. The boronate-protected Nap (PNap) can exploit increased levels of H 2 O 2 in HepG2 cells to in situ release Nap followed by its efflux via conjugation with reduced glutathione (GSH), allowing that the Nap-GSH adduct works as a Cu(II) ionophore to induce continuously GSH depletion via a reduction-dependent releasing of Cu(I) by GSH. This strategy endows PNap with the unprecedented ability to hit multi-redox characteristics (increased levels of H 2 O 2 , GSH and copper) of HepG2 cells, leading to ROS generation preferentially in HepG2 cells along with their selective death. Image 1 • A H 2 O 2 -activated Cu(II) pro-ionophore strategy was first used for developing pro-oxidative anticancer agent. • The protected naphthazarin (PNap) can be selectively activated by H 2 O 2 in HepG2 cells. • The strategy allows PNap with the ability to hit multi-redox characteristics of HepG2 cells. • PNap plus Cu(II) induced selective ROS generation in HepG2 cells. • Mechanisms by which PNap plus Cu(II) killed HepG2 cells selectively were described. [ABSTRACT FROM AUTHOR]

Altered redox homeostasis including higher levels of copper, reduced glutathione (GSH) and reactive oxygen species (ROS) in cancer cells than in normal cells illustrates their redox vulnerability, and has opened a window for developing prooxidative anticancer agents (PAAs) to hit this status. However, how to design PAAs with high selectivity in killing cancer cells over normal cells remains a challenge. Herein we designed a 3-hydroxyflavone-inspired copper pro-ionophore ( PHF ) as a potent PAA based on the GSH-mediated conversion of 2,4-dinitrobenzenesulfonates to enols. Mechanistic investigation reveals that it is capable of exploiting increased levels of GSH in cancer cells to in situ release an active ionophore, 3-hydroxyflavone, inducing redox imbalance (copper accumulation, GSH depletion and ROS generation) and achieving highly selective killing of cancer cells upon specific transport of small amounts of Cu(II). To the best of our knowledge, it is the first example of Cu(II) pro-ionophore type of PAA which hits (changes) the three birds (abnormal copper, GSH and ROS levels in cancer cells) with one stone ( PHF ) in terms of its ability to induce preferentially redox imbalance of cancer cells by copper accumulation, GSH depletion and ROS generation. [ABSTRACT FROM AUTHOR]