Isolation and characterization of feruloylated oligosaccharides from Phyllostachys acuta and in vitro antioxidant activity.

Feruloylated oligosaccharides (FOs) generated by decomposing plant hemicellulose, offer a wide range of potential applications in both the food and biomedical areas. As a graminaceous plant, bamboo is rich in hemicellulose. However, the structural composition and activity studies of FOs from it were rarely reported. In this study, FOs from Phyllostachys acuta (pFOs) obtained by enzymatic hydrolysis were isolated by AmberliteXAD-2 and C18 SPE columns. Then, pFOs were qualitatively and quantitatively analyzed by UPLC-ESI-MS/MS after labeled by 3-Amino-9-ethyl-carbazole (AEC), and the chemical antioxidant activity of pFOs and effects of pFOs on H2O2-induced oxidative damage were investigated. Finally, 14 of pFOs isomers were distinguished and identified, of which 10 did not contain hexoses and 4 did, and the three most abundant pFO structures were 12 (Iso 7, F1A1X2H2-AEC, 29.04 %), 11 (Iso 6, F1A1X1H2-AEC, 17.96 %), and 4 (Iso 3-1, F1A1X3-AEC, 15.57 %). The results of antioxidant studies showed that pFOs possessed certain reducing power, scavenging DPPH radicals, scavenging superoxide anion radicals, and scavenging hydroxyl radicals. Among them, the ability to clear DPPH radicals was particularly significant. pFOs significantly reduced the viability of RAW264.7 cells after H2O2 induction, whereas pFOs had a significant protective effect (p < 0.001). pFOs increased the viability of T-AOC and SOD enzymes in oxidatively damaged cells, as well as had a significant inhibition effect on ROS elevation (p < 0.001). This study lays the foundation for the structural analysis and antioxidant activity evaluation of bamboo-derived feruloyl oligosaccharides for their application in food and pharmaceutical fields.

The Mechanism of Catalpol to Improve Oxidative Damage of Dermal Fibroblasts Based on Nrf2/HO-1 Signaling Pathway.

Objective: Catalpol, as a natural medicine small-molecule drug, has been proven to have anti-inflammatory and antioxidant pharmacological effects. Methods: The effect of catalpol on oxidative damage of mouse epidermal fibroblast L929 model and its mechanism were investigated by using hydrogen peroxide model, CCK8 method, flow cytometry, and Western blot. Results: The effect of catalpol on Nrf2/HO-1 signaling pathway was further studied to improve oxidative stress in cell models. The results showed that catalpol had no cytotoxicity to L929 cells, and inhibited the apoptosis of L929 cells after oxidative damage in a concentration-dependent manner, thus playing a role in cell protection. The oxidative damage of cells was inhibited by up-regulating the expression of the signature protein of Nrf2/HO-1 signaling pathway and inhibiting the interstitial formation of cells. Conclusion: This study is a preliminary study on the protective function of catalpol against oxidation and apoptosis in dermal fibroblasts, which can provide a theoretical basis and drug guidance for promoting skin wound healing in the later stage.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

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Kaempferol Derivatives from Hippophae rhamnoides Linn. Ameliorate H2O2-Induced Oxidative Stress in SH-SY5Y Cells by Upregulating Nrf2.

As a medicinal and edible resource, Hippophae rhamnoides Linn. subsp. sinensis Rousi is rich in bioactive secondary metabolites, including flavonoids and their derivatives, which offer protective effects against oxidative damage. This study reported the isolation of three new kaempferol derivatives from the seed residue of H. rhamnoides - Hippophandine A, B, and C (compounds 1-3). Their structures were elucidated by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), nuclear magnetic resonance (NMR), and chemical analyses. The compounds were evaluated for their ability to mitigate hydrogen peroxide (H2O2)-induced cell death in SH-SY5Y cells. The results elucidated that Hippophandine A-C at concentrations of 1, 5, and 10 µM reduced the levels of malondialdehyde (MDA) and increased the activity of antioxidative enzymes, such as superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Furthermore, they significantly altered the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1), which is an indicator of redox detection in H2O2-induced SH-SY5Y.

Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

Azaphilone pigments from the marine-derived Penicillium sclerotium UJNMF 0503 and their neuroprotective potential against H2O2-induced cell apoptosis through modulating PI3K/Akt pathway.

Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.

Free radical scavenging activities of verbascoside and isoverbascoside from the leaves of Odontonema strictum (Acanthaceae).

The aqueous extract of the leaves of Odontonema strictum, a plant from tropical regions, is used by traditional physicians in Burkina Faso for its antihypertensive properties. Verbascoside and isoverbascoside, known phenylpropanoid glycosides with high solubility in water, have been isolated from the leaves. We evaluated their antioxidant properties in vitro by radical scavenging using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2). Verbascoside and isoverbascoside demonstrated high levels of DPPH radical scavenging activity, with IC50 values of 0.09 ± 0.03 µg/mL and 0.16 ± 0.07 µg/mL, respectively, compared to 0.05 ± 0.0 µg/mL for ascorbic acid as a control. These two phenylpropanoid glycosides were also more potent (2.6 ± 0.36 µg/mL and 3.0 ± 0.01 µg/mL) in scavenging H2O2 than the ascorbic acid control (4.1 ± 0.97 µg/mL). This is the first time that the antioxidant properties of verbascoside and isoverbascoside from O. strictum have been evaluated. These results can explain the use of this plant for hypertension in folk medicine.

Antioxidant, antimicrobial, cytotoxic and protective effects of truffles.

Fungi can be used as a potent chemotherapeutic agent to treat various cancers. In current study acetone and methanol extracts of Terfezia claveryi, Terfezia boudieri, Terfezia olbiensis, Picoa lefebvrei, Picoa juniperi were used to assess total phenolic contents, antioxidant activity, ion-chelating impact, antimicrobial activity, the cytotoxic and protective effects. Both methanol and acetone extracts of T. boudieri had the highest FRAP and DPPH scavenging abilities. Dose-dependent increased ion-chelating impact of all tested truffles species was found. Extracts of T. boudieri, T. claveryi, and T. albiensis exhibited higher antimicrobial activities. T. claveryi and T. boudieri showed the highest protective effects against H2O2-induced genotoxicity (P < 0.05), in S. cerevisiae BY4741. The least protective effect was showed by the acetone extracts of T. olbiensis (144 ± 8); methanol extracts of P. lefebvrei (140 ± 8) and P. juniperi (140 ± 10). MCF 7 cells showed more sensitivity against to methanol extracts of T. boudieri at 10-100 µg/mL concentrations. HepG2 cells showed more sensitivity against the methanolic extracts of T. boudieri at both doses. Overall, P. lefebvrei and P. juniperi extracts had the least cytotoxic effects. The species of Terfezia exhibit significant protective effects against DNA damage and also have the potential of cytotoxicity effects.

Protective Effect of Fasudil on Hydrogen Peroxide-Induced Oxidative Stress Injury of H9C2 Cardiomyocytes.

OBJECTIVE: Oxidative damage is a pathological factor that causes cardiovascular damage in the clinic and is increasingly serious. This study focused on the effect of fasudil on H2O2-induced oxidative damage in cardiomyocytes. MATERIALS AND METHODS: H9C2 cardiomyocytes were cultured in vitro and divided into three groups: control group (Con group), H2O2 treatment (H2O2 group), and fasudil and H2O2 cotreatment (H2O2+fasudil group). The content levels of LDH and MDA in the supernatant were detected, and the morphology of H9C2 cardiomyocytes was observed by light microscopy. 8-OHdG staining was observed by a fluorescence inversion microscope. Cell Counting Kit (CCK-8), western blotting, real-time polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to investigate the effect of fasudil on the Rho/ROCK signaling pathway. RESULTS: Our results showed that after H2O2 treatment, the H9C2 cardiomyocytes were irregular in shape and elliptical. But the morphology of the H2O2+fasudil group was similar to that of the Con group. The green fluorescence of the H2O2 group was significantly enhancer than that of the Con group, while the green fluorescence of the H2O2+fasudil group was weaker than those of the H2O2 group. By detecting the supernatant, it was found that the contents of LDH were significantly increased, and the contents of SOD and CAT in the H2O2 group were significantly decreased. And the expression of antioxidant indicators in the H2O2 group was significantly decreased by western blotting. The results of RT-PCR showed that SOD1 and SOD2 mRNA in the H2O2 group was significantly reduced, and the contents of GPX1 and GPX3 in the H2O2 group were significantly decreased by enzyme-linked immunosorbent assay (ELISA). The expression of ROCK1, ROCK2, and downstream phosphorylation of myosin phosphatase target subunit-1 (p-MYPT-1) was significantly increased in the H2O2 group, while fasudil inhibited the increase of ROCK1, ROCK2, and p-MYPT-1. CONCLUSIONS: Fasudil can inhibit the Rho/ROCK signaling pathway induced by H2O2 and reduce oxidative stress response, inhibit apoptosis, and improve antioxidant enzyme activity in H9C2 cardiomyocytes thereby delaying cell senescence.

Hypocrellin B-based activatable photosensitizers for specific photodynamic effects against high H2O2-expressing cancer cells.

A novel tumor-related biomarker, a H2O2-activatable photosensitizer 4 based on the 1,3-dicarbonyl enol moieties of hypocrellin B (3), was designed and synthesized. The photosensitizer 4 showed a blue-shifted absorption band compared with 3, and showed negligible photosensitizing ability without H2O2. However, the release of 3 from 4 by the reaction with H2O2 regenerated the photosensitizing ability. Furthermore, 4 exhibited selective and effective photo-cytotoxicity against high H2O2-expressing cancer cells upon photo-irradiation with 660 nm light, which is inside the phototherapeutic window.

Protective Effects of Mogroside V on Oxidative Stress Induced by H2O2 in Skin Fibroblasts.

PURPOSE: Damage caused by oxidative stress leads to the premature aging of cells. Mogrosides, the main active components of Siraitia grosvenorii, have strong antioxidant activity; however, it is unclear whether mogroside V (MV) exerts these effects in skin cells. This was investigated in the present study by evaluating the protective effects of MV against oxidative damage induced by hydrogen peroxide (H2O2) in skin fibroblasts. METHODS: Mouse skin fibroblasts (MSFs) were treated with H2O2 and cell viability, total antioxidant capacity, reactive oxygen species (ROS) production, malondialdehyde (MDA) content, and antioxidant enzyme activity were assessed. RESULTS: Treatment with MV reduced the ROS level and MDA content in MSFs treated with H2O2. This was accompanied by increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities. CONCLUSION: MV reduces H2O2-induced oxidative stress and enhances endogenous antioxidant activity in skin fibroblasts. Thus, MV can potentially be used as an ingredient in anti-aging cosmetic products.

Methylcobalamin Protects Melanocytes from H2O2-Induced Oxidative Stress by Activating the Nrf2/HO-1 Pathway.

PURPOSE: Oxidative stress is considered a major determinant in the pathogenesis of vitiligo. Methylcobalamin (MeCbl) is an activated form of vitamin B12 that regulates inflammatory factors, counters oxidative stress, and reduces apoptosis in many disease models. However, the specific mechanism of MeCbl repigmentation against vitiligo is unknown. In this study, we explored the effect of MeCbl on melanocytes following hydrogen peroxide (H2O2)-induced oxidative stress. METHODS: We established an oxidative stress model using the immortalized human normal melanocyte cell line PIG1. We used a Cell Counting Kit-8 (CCK-8) to detect drug cytotoxicity, and we measured the melanin content of cells using the NaOH method. Intracellular oxidative damage was assessed by flow cytometry and antioxidant enzyme detection kits. In addition, we assessed the presence of apoptosis by flow cytometry and Western blots. We explored the underlying mechanisms of MeCbl during oxidative stress in melanocytes by analyzing the results of experiments based on real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, and laser scanning confocal immunofluorescence microscopy. Finally, we repeated the experiments after applying an inhibitor to block the Nrf2 pathway. RESULTS: We found that MeCbl treatment enhanced cell viability, increased melanin content, reduced intracellular reactive oxygen species (ROS) accumulation, increased the activities of antioxidant enzyme superoxide dismutase (SOD) and catalase (CAT), reduced melanocyte apoptosis, and up-regulated the expression of the Nrf2/HO-1 pathway. Moreover, the protective effects of MeCbl were significantly weakened after inhibiting the Nrf2/HO-1 pathway. CONCLUSION: Our results indicate that MeCbl attenuated the H2O2-induced oxidative stress in melanocytes by activating the Nrf2/HO-1 pathway, this suggests that MeCbl may be an effective treatment against vitiligo.

An Investigation into the Interaction between Double Hydroxide-Based Antioxidant Benzophenone Derivatives and Cyclooxygenase 2.

Cyclooxygenases 2 (COX2) is a therapeutic target for many inflammation and oxidative stress associated diseases. A high-throughput technique, biolayer interferometry, was performed to primarily screen the potential COX2 binding activities of twelve newly synthesized double hydroxide-based benzophenone derivatives. Binding confirmation was achieved by molecular docking and multi-spectroscopy studies. Such a combined method provided a comprehensive understanding of binding mechanism and conformational changes. Compounds DB2, SC2 and YB2 showed effective COX2 binding activity and underlined the benefits of three phenolic hydroxyl groups adjacent to each other on the B ring. The twelve tested derivatives were further evaluated for antioxidant activity, wherein compound SC2 showed the highest activity. Its concentration for the 50% of maximal effect (EC50) value was approximately 1000 times greater than that of the positive controls. SC2 treatment effectively improved biochemical indicators caused by oxidative stress. Overall, compound SC2 could serve as a promising candidate for further development of a new potent COX2 inhibitor.

Formulation of liposomes loading lentisk oil to ameliorate topical delivery, attenuate oxidative stress damage and improve cell migration in scratch assay.

Pistacia lentiscus L. is a sclerophyllous shrub capable of growing under harsh climatic conditions especially in the Mediterranean Basin. Different products can be obtained from this plant, such as essential oil, mastic gum or even fixed oil. The last is well known for its flavor which is mainly exploited in the food industry. Additionally, it has been traditionally used in the treatment of skin diseases, but, at the moment, any suitable formulation for skin delivery has been formulated and its biological effects was not deeply confirmed. Given that, in the present study, the lentisk oil has been formulated in liposomes at different concentrations (10, 20, 30 mg/ml) and their physicochemical, technological and main biological properties have been evaluated. Vesicles were prepared by using natural soy lecithin and a green and organic solvent free method, thus obtaining spherical, small (~ 118 nm), homogeneously dispersed (0.27) and highly negatively charged (~ -62 mV) vesicles. The used amount of oil loaded in liposomes (10, 20, 30 mg/ml) modulated the penetration ability of vesicles in the skin, favoring the deposition of the payload in the deeper strata. The loading in the vesicles potentiated the ability of oil to counteract the damaging effects caused by hydrogen peroxide in keratinocytes and fibroblasts and facilitate their migration in a cell monolayer lesion. Overall findings suggested that the incorporation of lentisk oil in liposomes made from soy lecithin can be an alternative and natural approach to exploit it in pharmaceutical ad cosmetical applications and manufacturing natural products suitable for the treatment of skin lesions.

Radical Scavenging Potential of the Phenothiazine Scaffold: A Computational Analysis.

The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM-ORSA (Quantum Mechanics-based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO. , HOO. , and CH3 OO. . PS, PSE, and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusion-controlled regime processes. For the HO. radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO. and CH3 OO. , the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE, and SET for PTE. The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO. ). Therefore, PS, PSE, and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites.

Design, synthesis and biological activities of benzo[d]imidazo[1,2-a]imidazole derivatives as TRPM2-specfic inhibitors.

Transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer and neurodegenerative diseases. However, the lack of specific inhibitors impedes the development of TRPM2 targeted therapeutic agents. To develop a selective TRPM2 inhibitor, three-dimensional similarity-based screening strategy was employed using the energy-minimized conformation of non-selective TRPM2 inhibitor 2-APB as the query structure, which resulted in the discovery of a novel tricyclic TRPM2 inhibitor Z-4 with benzo[d]imidazo[1,2-a]imidazole skeleton. A series of Z-4 derivatives were subsequently synthesized and evaluated using calcium imaging and electrophysiology approaches. Among them, preferred compounds ZA10 and ZA18 inhibited the TRPM2 channel with micromolar half-maximal inhibitory concentration values and exhibited TRPM2 selectivity over the TRPM8 channel, TRPV1 channel, InsP3 receptor and Orai channel. The analysis of structure-activity relationship provides valuable insights for further development of selective TRPM2 inhibitors. Neuroprotection assay showed that ZA10 and ZA18 could effectively reduce the mortality of SH-SY5Y cells induced by H2O2. These findings enrich the structure types of existing TRPM2 inhibitors and might provide a new tool for the study of TRPM2 function in Reactive oxygen species (ROS) -related diseases.

Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders.

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

Evaluation of Antioxidative Mechanisms In Vitro and Triterpenes Composition of Extracts from Silver Birch (Betula pendula Roth) and Black Birch (Betula obscura Kotula) Barks by FT-IR and HPLC-PDA.

Silver birch, Betula pendula Roth, is one of the most common trees in Europe. Due to its content of many biologically active substances, it has long been used in medicine and cosmetics, unlike the rare black birch, Betula obscura Kotula. The aim of the study was therefore to compare the antioxidant properties of extracts from the inner and outer bark layers of both birch trees towards the L929 line treated with acetaldehyde. Based on the lactate dehydrogenase test and the MTT test, 10 and 25% concentrations of extracts were selected for the antioxidant evaluation. All extracts at tested concentrations reduced the production of hydrogen peroxide, superoxide anion radical, and 25% extract decreased malonic aldehyde formation in acetaldehyde-treated cells. The chemical composition of bark extracts was accessed by IR and HPLC-PDA methods and surprisingly, revealed a high content of betulin and lupeol in the inner bark extract of B. obscura. Furthermore, IR analysis revealed differences in the chemical composition of the outer bark between black and silver birch extracts, indicating that black birch may be a valuable source of numerous biologically active substances. Further experiments are required to evaluate their potential against neuroinflammation, cancer, viral infections, as well as their usefulness in cosmetology.

Neurotrophic Effect of Magnesium Comenate in Normal and under Conditions of Oxidative Stress in Culture of Chicken Spinal Ganglia.

The neurotrophic properties of magnesium comenate were studied under standard conditions and under conditions of oxidative stress. It was found that magnesium comenate has a stimulating effect on the neurotrophic processes of the spinal ganglia under normal conditions and under conditions of oxidative stress. Under standard conditions, magnesium comenate exhibits neurotrophic activity at a concentration of 0.0001 mM, under conditions of oxidative stress, magnesium comenate exhibits neurotrophic activity at concentration 0.1 mM.

Selective targeting of cancer cells using a hydrogen peroxide-activated Hsp90 inhibitor.

Heat shock protein 90 (Hsp90) plays an important role in cancer cell proliferation, survival, and migration by regulating the maturation and stabilization of numerous oncoproteins. Despite significant efforts in developing Hsp90 inhibitors, none of these have been approved for clinical use, mostly due to toxicity, such as liver, cardiac, and retinal toxicity. To avoid undesirable toxicity, we herein report a hydrogen peroxide-activated Hsp90 inhibitor, Boro-BZide (3), which is capable of selectively targeting cancer cells over normal cells. Boro-BZide (3) can be activated by high levels of hydrogen peroxide, releasing its parent active Hsp90 inhibitor. The mechanism of action was determined by a series of experiments including fluorescence polarization assay, cell viability assay, western blotting, high-pressure liquid chromatography (HPLC), and fluorescence-activated cell sorting (FACS) analysis. These efforts ultimately led to the identification of a novel hydrogen peroxide-activated Hsp90 prodrug with improved therapeutic index, which was less prone to furnish unwanted adverse effects. This hydrogen peroxide-responsive prodrug strategy will be beneficial for overcoming the toxicity hurdles of Hsp90 inhibitors for clinical application.