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.
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•PHF is the first case of Cu(II) pro-ionophore type of prooxidative anticancer agent.•PHF can be selectively activated by GSH in cancer cells over in normal cells.•PHF plus Cu(II) can preferentially induce redox imbalance of cancer cells.•PHF plus Cu(II) can high selectively and synergistically kill cancer cells.
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 (H2O2)-activated Cu(II) pro-ionophore strategy to develop naphthazarin (Nap) as such type of PAAs based on the H2O2-mediated conversion of boronate to free phenol. The boronate-protected Nap (PNap) can exploit increased levels of H2O2 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 H2O2, GSH and copper) of HepG2 cells, leading to ROS generation preferentially in HepG2 cells along with their selective death.
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•A H2O2-activated Cu(II) pro-ionophore strategy was first used for developing pro-oxidative anticancer agent.•The protected naphthazarin (PNap) can be selectively activated by H2O2 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.
Developing concise theranostic prodrugs is highly desirable for personalized and precision cancer therapy. Herein we used the glutathione (GSH)-mediated conversion of 2,4-dinitrobenzenesulfonates to ...phenols to protect a catechol moiety and developed stable pro-catechol-type diphenylpolyenes as small molecule-based prooxidative anticancer theranostic prodrugs. These molecules were synthesized via a modular route allowing creation of various pro-catechol-type diphenylpolyenes. As a typical representative, PDHH demonstrated three unique advantages: (1) capable of exploiting increased levels of GSH in cancer cells to in situ release a catechol moiety followed by its in situ oxidation to o-quinone, leading to preferential redox imbalance (including generation of H2O2 and depletion of GSH) and final selective killing of cancer cells over normal cells, and is also superior to 5-fluorouracil and doxorubicin, the widely used chemotherapy drugs, in terms of its ability to kill preferentially human colon cancer SW620 cells (IC50 = 4.3 μM) over human normal liver L02 cells (IC50 = 42.3 μM) with a favourable in vitro selectivity index of 9.8; (2) permitting a turn-on fluorescent monitoring for its release, targeting mitochondria and therapeutic efficacy without the need of introducing additional fluorophores after its activation by GSH in cancer cells; (3) efficiently targeting mitochondria without the need of introducing additional mitochondria-directed groups.
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•Using the GSH-mediated conversion of DNBS to phenols to protect a catechol moiety.•Designing GSH-activated PDHH as a concise theranostic prodrug.•Monitoring for its release, targeting and therapeutic efficacy by a turn-on fluorescent.•Identifying PDHH as a potent prooxidative anticancer prodrug.•Identifying the diphenylpolyene skeletons as mitochondria-directed groups.
This work highlights the use of push–pull hydroxylphenylpolyenylpyridinium fluorophores coupled with trimethyl lock quinone to engineer the ratiometric two-photon probes for cellular and intravital ...imaging of mitochondrial NAD(P)H:quinone oxidoreductase 1 (NQO1), a critical antioxidant enzyme responsible for detoxifying quinones. As a typical representative, QBMP showed favorable binding with NQO1 with a Michaelis constant of 12.74 μM and exhibited a suite of superior properties, including rapid response (4 min), large Stokes shift (162 nm), ultralow detection limit (0.9 nM), favorable two-photon cross section for the released fluorophore (70.5 GM), and deep tissue penetration (225 μm) in fixed brain tissues. More importantly, this probe was successfully applied for distinguishing different NQO1-expressing cancer and normal cells, revealing decreased NQO1 activity in a cellular Parkinson’s disease model, screening NQO1 inducers as neuroprotective agents, and imaging of NQO1 in live mouse brain.
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.
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•Structural basis of flavones as Cu(II) ionophores is 3(or 5)-hydroxy-4-keto group.•3-Hydroxyflavone (3-HF) surfaced as a potent Cu(II) ionophore to kill cancer cells.•The first step of 3-HF as a Cu(II) ionophore is sequential proton-loss chelation.•The second step of 3-HF as a Cu(II) ionophore is GSH-driving copper releasing.•The third step of 3-HF as a Cu(II) ionophore is protonation-dependent efflux.
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.
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•Showing the significance of a keto-enol moiety for developing Cu(II) ionophores.•Keto-enol-based modification on piperlongumine to generate the designed PL-I.•Its keto-enol structure was well-identified by NMR and theoretical calculations.•This molecule in the enol form deprotonated can effectively complex Cu(II).•This molecule triggers redox imbalance and death of HepG2 cells.
Compared with normal cells, cancer cells harbor increased levels of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), and therefore are more vulnerable to further ROS production. This ...biochemical difference favors the idea of developing new powerful selective prooxidative anticancer agents. However, it still remains a challenge to design them by targeting this difference. Herein, we report the designed dichlorobinaphthoquinone as a prooxidative anticancer agent which is capable of exploiting increased levels of H2O2 of cancer cells to produce in situ lethal hydroxyl radicals (HO•) and thereby kill them selectively, a design strategy inspired from Zhu et al.’s work on the molecular mechanism for metal-independent production of HO•.
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•Designing prooxidative anticancer agents by metal-independent production of HO•.•BQ-DC was designed based on the skeleton of natural conocurvone.•Preferential killing of cancer cells over normal cells by the designed BQ-DC.•BQ-DC can exploit increased levels of H2O2 of cancer cells to in situ produce HO•.•The H2O2-responsive formation of HO• was evidenced by a series of experiments.
Four novel compounds were designed by “tailoring” 3,3′‐dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 ...(2,3,6,2′,3′,6′‐hexamethyl‐4,4′‐dihydroxy‐trans‐stilbene) was concisely synthesized in a one‐pot Stille–Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI‐H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol‐inspired antiproliferative agents.
Four novel compounds were designed by “tailoring” 3,3′‐dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 was concisely synthesized by a one‐pot Stille–Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity (see figure).
A solid complex,readily prepared from commercially available sodium triphenylphosphine-m-sulfonate（TPPMS） and carbon tetrabromide,can be used as an easily recoverable and reusable catalyst system for ...one-pot condensation of 2-naphthol with aldehydes to construct 14-aryl（alkyl）-14H-dibenzoa j-xanthene derivatives and one-pot condensation of 2-naphthol with aldehydes and cyclic 1 3-dicarbonyl compounds to construct 12-aryl（alkyl）-8 9 10 12-tetrahydrobenzoaxanthen-11-one derivatives.
Planarians exhibit an extraordinary ability to regenerate lost body parts which is attributed to an abundance of pluripotent somatic stem cells called neoblasts. In this article, we report a ...transcriptome sequence of a Planaria subspecies
Dugesia japonica derived by high-throughput sequencing. In addition, we researched transcriptome changes during different periods of regeneration by using a tag-based digital gene expression (DGE) system. Consequently, 11,913,548 transcriptome sequencing reads were obtained. Finally, these reads were eventually assembled into 37,218 unique unigenes. These assembled unigenes were annotated with various methods. Transcriptome changes during planarian regeneration were investigated by using a tag-based DGE system. We obtained a sequencing depth of more than 3.5
million tags per sample and identified a large number of differentially expressed genes at various stages of regeneration. The results provide a fairly comprehensive molecular biology background to the research on planarian development, particularly with regard to its regeneration progress.
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