Synthesis of bioactive evodiamine and rutaecarpine analogues under ball milling conditions.

Mechanochemical reactions achieved by processes such as milling and grinding are promising alternatives to traditional solution-based chemistry. This approach not only eliminates the need for large amounts of solvents, thereby reducing waste generation, but also finds applications in chemical and materials synthesis. The focus of this study is on the synthesis of quinazolinone derivatives by ball milling, in particular evodiamine and rutaecarpine analogues. These compounds are of interest due to their diverse bioactivities, including potential anticancer properties. The study examines the reactions carried out under ball milling conditions, emphasizing their efficiency in terms of shorter reaction times and reduced environmental impact compared to conventional methods. The ball milling reaction of evodiamine and rutaecarpine analogues resulted in yields of 63-78% and 22-61%, respectively. In addition, these compounds were tested for their cytotoxic activity, and evodiamine exhibited an IC50 of 0.75 ± 0.04 µg mL-1 against the Ca9-22 cell line. At its core, this research represents a new means to synthesise these compounds, providing a more environmentally friendly and sustainable alternative to traditional approaches.

Antrodia cinnamomea prevents ovariectomized-promoted bone loss by inhibiting osteoclast formation.

Osteoporosis is a common bone disease in aging populations, particularly in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are linked with a variety of adverse effects. Antrodia cinnamomea extracts (ACE) are highly renowned for their anticancer, antioxidative, and anti-inflammatory properties. However, whether ACE-enriched anti-osteoporosis functions are largely unknown. In a preclinical animal model, we found that ovariectomy significantly decreased bone volume in the ovariectomized (OVX) rats. Administration of ACE antagonized OVX-induced bone loss. In addition, ACE reversed OVX-reduced biomechanical properties. The serum osteoclast marker also showed improvement in the ACE-treated group. In the cellular model, it was indicated that ACE inhibits RANKL-induced osteoclast formation. Taken together, ACE seems to be a hopeful candidate for the development of novel anti-osteoporosis treatment.

Briavioids E-G, Newly Isolated Briarane-Diterpenoids from a Cultured Octocoral Briareum violaceum.

The chemical screening of a cultured soft coral, Briareum violaceum, led to the isolation of eight natural, briarane-related diterpenoids, including three unreported metabolites, briavioids E-G (1-3), and five known briaranes, briacavatolides B (4) and C (5), briaexcavatin L (6), briaexcavatolide U (7) and briarenol K (8). The structures of briaranes 1-8 were established using spectroscopic methods. The absolute configuration of briavioid A (9), obtained in a previous study, was reported for the first time in this study by a single-crystal X-ray diffraction analysis using a copper radiation source. The anti-inflammatory activity of briaranes 1 and 2 and briaranes 4-8 was evaluated by screening their inhibitory ability against the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells.

Regiodivergent Synthesis of Methylene and Methyl Ring-Fused Isoquinolinones: Base-Promoted Isomerization of N-Allyl Amides.

Methylene and methyl tricyclic isoquinolinones were selectively prepared using a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a base- and temperature-controlled Heck reaction catalyzed by palladium(0). Exo- to endo-double-bond migration in isoquinolinones was achieved with 93-99% yields by treatment of the Heck products with Cs2CO3 in dimethyl sulfoxide (DMSO) at 150 °C. A probable mechanism for Cs2CO3-promoted olefin isomerization was proposed and examined using D-isotope labeling experiments. Finally, yuanamide, a 13-methyl-8-oxoprotoberberine alkaloid, was synthesized using the palladium-catalyzed aza-Wacker/Heck/migration sequence.

Novel Aurora A Kinase Inhibitor Fangchinoline Enhances Cisplatin-DNA Adducts and Cisplatin Therapeutic Efficacy in OVCAR-3 Ovarian Cancer Cells-Derived Xenograft Model.

Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin-DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.

Targeting PSEN1 by lnc-CYP3A43-2/miR-29b-2-5p to Reduce ß Amyloid Plaque Formation and Improve Cognition Function.

Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates ß-amyloid (Aß) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to reduce Aß levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer's disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aß accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aß reduction.

Bioactive polyketides from the pathogenic fungus of Epicoccum sorghinum.

MAIN CONCLUSION: We discovered and identified a series of characteristic substances, including one new polyketide, epicorepoxydon B, of the important pathogenic fungus, Epicoccum sorghinum, of sorghum. The fungal extract and some isolated polyketides are sensitive to a malignant triple-negative breast cancer cell line, MDA-MB-231. Sorghum (Kaoliang) grain is an important crop with high economic value and several applications. In Taiwan, sorghum has been used in the wine industry, and "Kinmen Kaoliang Liquor" is a well-known Asian brand. Fungal contamination is one of the major threats affecting the production of sorghum grain resulting in economic losses as well as human and animal health problems. Several fungal species can infect sorghum grain and generate some toxic secondary metabolites. Epicoccum sorghinum is one of the major fungal contaminants of sorghum grains and a potent producer of mycotoxins such as tenuazonic acid (TeA). However, except for TeA, few studies focused on chemical compounds produced by this fungus. To explore the potential biological and toxic effects of E. sorghinum, a chemical investigation was carried out on the ethyl acetate extract of the fungus because it showed cytotoxic activity against a triple-negative breast cancer cell line, MDA-MB-231 (54.82% inhibition at 20 µg/mL). One new polyketide, epicorepoxydon B (1), along with six known compounds including 4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-hydroxymethyl-2-cyclohexenl-one (2), epicorepoxydon A (3), 3-hydroxybenzyl alcohol (4), 6-methylsalicylic acid (5), gentisyl alcohol (6), and 6-(hydroxymethyl)benzene-1,2,4-triol (7) were obtained, and their structures were established by the interpretation of their MS and NMR spectroscopic data. The cytotoxic activity of all isolated polyketides 1-7 was evaluated, and compounds 2, 6, and 7 exhibited potent activities against A549, HepG2, and MDA-MB-231 human cancer cell lines with IC50 value ranging from 1.86 to 18.31 µM. The structure-activity relationship of the isolated compounds was proposed.

8-Hydroxybriaranes from Octocoral Briareum stechei (Briareidae) (Kükenthal, 1908).

Chemical investigation of the octocoral Briareum stechei, collected in the Ie Island, Okinawa, Japan, resulted in the isolation of a new briarane-type diterpenoid, briastecholide A (1), as well as the previously reported metabolites, solenolide C (2) and briarenolide S (3). The structures of briaranes 1-3 were characterized through spectroscopic analysis, and the absolute configuration of 2 was corroborated by a single-crystal X-ray diffraction analysis. Briarane 3 exhibited bioactivity against the protein expression of inducible nitric oxide synthase (iNOS).

Enzyme-Digested Peptides Derived from Lates calcarifer Enhance Wound Healing after Surgical Incision in a Murine Model.

Surgical wounds are common injuries of skin and tissues and usually become a clinical problem. Until now, various synthetic and natural peptides have been widely explored as potential drug candidates for wound healing. Inhibition of the TNF-α signaling pathway and promotion of angiogenesis are suggested to be involved in their effects. Angiogenesis at the wound site is one of the essential requisites for rapid healing. In the present study, a novel peptide extract derived from the natural source Lates calcarifer, commonly known as sea bass or barramundi, was evaluated for its wound healing property. The specific acidic and enzymatic approaches were employed for producing sea bass extract containing small size peptides (molecular weight ranging from 1 kD to 5 kD). The cytotoxicity of the extract was examined in HaCaT and NIH3T3. After this, the effects of enzyme digested peptide extracts of sea bass on wound healing in mice were investigated. The peptide extracts (660 and 1320 mg/kg/day) and control protein (1320 mg/kg/day) was orally given to the wounded mice, respectively, for 12 days. The surgical method was improved by implanting a silicone ring at the wound site. The ring avoided the contracting effect in murine wounds, making it more closely related to a clinical condition. The results showed promising improvement at the wound site in mice. Sea bass peptide extracts accelerated the wound healing process and enhanced the microvessel formation at the wound site. The remarkable effects of this novel sea bass peptide extract in healing traumatic injuries revealed a new option for developing wound management.

Synthesis of Novel Spiro-Tetrahydroquinoline Derivatives and Evaluation of Their Pharmacological Effects on Wound Healing.

A highly diastereoselective method for the synthesis of novel spiro-tetrahydroquinoline derivatives is reported here, using a one-pot reaction method. All compounds were characterized by 1H-nuclear magnetic resonance (NMR) and mass spectroscopy, and their stereo configurations were confirmed by X-ray analysis. These activities of these derivatives were then tested in human keratocyte cells. The responses of cells to treatment with selected compounds were studied using scratch analysis, and the compounds were tested in a mouse excision wound model. Three of the derivatives demonstrated significant wound-healing activities.

The protoapigenone analog WYC0209 targets CD133+ cells: A potential adjuvant agent against cancer stem cells in urothelial cancer therapy.

Urothelial carcinoma (UC) is one of the highest incidence cancers that rank the fourth commonly diagnosed tumors worldwide. The unresectable lesions that are resistant to therapeutic interventions is the major cause leading to death. Previous studies had shown that the resistance and metastatic consequence may arise from cancer stem-like cells population. The phytochemical flavonoids have promised bioactivity and potent anti-carcinogenic effects, and trap great attentions for cancer chemoprevention and/or adjuvant chemotherapy. However, the mechanisms of flavonoids on cancer stemness is still obscured. In this study, we analyzed the biofunctional effects of as-prepared flavonoid derivative-WYC0209 on T24, BFTC905 and BFTC909 human UC cell lines. Our results demonstrated that WYC0209 significantly induced anti-cell viability on UC cells through decreased Akt/NFkB signaling. Moreover, WYC0209 enhanced the cell apoptosis through activated the caspase-3 activity and inactivated Bcl-xL expression. Interestingly, WYC0209 dramatically inhibited the cancer stem cells (CSCs) traits, including attenuation of side population and tumorsphere formation in which were through declined EMT-CSCs markers including MDR1, ABCG2 and BMI-1. We further validated the effects of WYC0209 on several CSC surface markers including CD133, CD44, SOX-2 and Nanog. Our results showed that WYC0209 markedly inhibited CD133 expressions in both transcriptional and translational levels. High expression levels of CD133 was also demonstrated in human upper tract UC specimens. In summary, our study showed that WYC0209 may potentially as an adjuvant agent to against CD133-driven UC CSCs and provide a beneficial strategy to against UC cancer therapeutics resistant.

Briarenols Q-T: Briaranes from A Cultured Octocoral Briareum stechei (Kükenthal, 1908).

Our continuous chemical study of a cultured octocoral Briareum stechei led to the isolation of four new briarane diterpenoids, briarenols Q-T (1-4). The structures of new metabolites 1-4 were established by spectroscopic methods, and compounds 3 and 4 were found to inhibit the generation of inducible nitric oxide synthase (iNOS) from RAW 264.7 stimulated by lipopolysaccharides (LPS).

Antrodia cinnamomea, a Treasured Medicinal Mushroom, Induces Growth Arrest in Breast Cancer Cells, T47D Cells: New Mechanisms Emerge.

Reported cases of breast cancer have skyrocketed in the last decades with recent advances in examination techniques. Brest cancer has become the second leading cause of mortality among women worldwide, urging the scientific community to develop or find new drugs from natural sources with potent activity and a reasonable safety profile to tackle this ailment. Antrodia cinnamomea (AC) is a treasured medicinal fungus which has attracted attention due to its potent hepatoprotective and cytotoxic activities. We evaluated the antiproliferative activity of the ethanol extract of artificially cultured AC (EEAC) on breast cancer cells (T47D cells) in vivo and in vitro. Ethanol extract of artificially cultured AC inhibited T47D cells' proliferation mediated by cell cycle arrest at G1 phase as well induced autophagy. Immunoblotting assay confirmed that EEAC not only decreased the expression of the cell-cycle-related proteins but also increased the expression of transcription factor FOXO1, autophagic marker LC3 II, and p62. Ethanol extract of artificially cultured AC mediated endoplasmic reticulum stress by promoting the expression of IRE1 (inositol-requiring enzyme 1α), GRP78/Bip (glucose regulating protein 78), and CHOP (C/EBP homologous protein). Apart from previous studies, HDACs (histone deacetylases) activity was inhibited as demonstrated by a cell-free system, immunoblotting, and immunofluorescence assays following EEAC treatment. The in vivo studies demonstrated that EEAC decreased tumor volume and inhibited tumor growth without any significant side effects. High performance liquid chromatography profile demonstrated similar triterpenoids compared to the profile of wild AC ethanol extract. The multiple targets of EEAC on breast cancer cells suggested that this extract may be developed as a potential dietary supplement targeting this debilitating disease.

The Antioxidant from Ethanolic Extract of Rosa cymosa Fruits Activates Phosphatase and Tensin Homolog In Vitro and In Vivo: A New Insight on Its Antileukemic Effect.

Rosa cymosa Tratt is a Chinese herbal remedy that is used in the treatment of diarrhea, burns, rheumatoid arthritis, and hemorrhage. Despite its use in Asian folk medicine, there are limited reports on the biological activity of R. cymosa fruits. This study focused on the investigation of the antitumor effect of the antioxidative ethanolic extract of R. cymosa fruits (RCE) along with its underlying mechanism of action. RCE showed a potent cytotoxic effect against Sup-T1 and Molt-4 lymphoblastic leukemia cells. In the xenograft animal model, the tumor size was significantly reduced to about 59.42% in the RCE-treated group in comparison with the control group. The use of RCE (37.5, 75, or 150 µg/mL) triggered apoptosis by 26.52-83.49%, disrupted mitochondrial membrane potential (MMP) by 10.44-58.60%, and promoted calcium release by 1.29-, 1.44-, and 1.71-fold compared with the control group. The extract induced redox oxygen species (ROS) generation through the elimination of Nrf2/Keap1/P62-mediated oxidative stress response. The loss of phosphatase and tensin homolog (PTEN) activation by RCE impaired PI3K/Akt/Foxo and Jak/Stat activation pathways, which contributed to tumorigenesis. These multiple targets of R. cymosa against hematologic cancer cells suggested its potential application as an antileukemic dietary supplement.

Bioactive Phenolic Components from the Twigs of Atalantia buxifolia.

Five new compounds named buxifoximes A-C (1-3), buxifobenzoate (4), and 7- O-(7'-peroxygeranyl) coumarin (5), together with 25 known compounds, were identified from the twigs of Atalantia buxifolia. Compounds 1-3 are unique secondary metabolites with the aldoxime functionality. The structures of the isolates were determined on the basis of spectroscopic data analyses, and the structure of 1 was confirmed by an X-ray single-crystallographic analysis. With respect to bioactivity, antidengue virus, anti-inflammatory, and cytotoxic activities of all purified compounds were tested and evaluated. Compound 1 showed a significant anti-inflammatory effect by inhibiting superoxide anion generation with an IC50 value of 4.8 ± 0.7 µM. Among the acridone alkaloids, 5-hydroxy- N-methylseverifoline (23) exhibited antidengue activity (IC50 = 5.3 ± 0.4 µM), and atalaphyllinine (20) demonstrated cytotoxicity (IC50 = 6.5 ± 0.0 µM) against the human liver cancer cell line, HepG2.

Bioactive Triterpenoids from the Leaves and Twigs of Lithocarpus litseifolius and L. corneus.

Phytochemical investigation of the leaves and twigs of Lithocarpus litseifolius and Lithocarpus corneus resulted in the isolation of four new triterpenoids (1: -4: ), three triterpenoids (5: -7: ) isolated from a natural source for the first time, and six known compounds (8: -13: ). In addition, four known triterpenoids (14: -17: ) were isolated from L. corneus. Compound 1: is a 3,4-seco-lupane-type triterpenoid, and compounds 2: -4: are lupane-type triterpenoids in different oxidation states. The structures of all isolated compounds were identified by spectroscopic methods, especially NMR and mass spectrometry data. The absolute configuration of 2: and 3: was confirmed by X-ray single crystallographic analysis. The anti-inflammatory activities of 1: -17: and anti-HIV activities of 2: -17: were evaluated. Among them, 3-epi-betulinic acid (8: ) showed a strong anti-HIV activity comparable to abacavir, a drug used for treating HIV/AIDS. 3,4-seco-4(23),20(29)-lupadiene-3,28-dioic acid (5: ) exhibited potent inhibition of superoxide-anion generation with 86.9 ± 2.8% inhibition at 1 µM.

Natural Product Chemistry of Gorgonian Corals of Genus Junceella⁻Part III.

The structures, names, bioactivities, and references of 82 natural products, including 48 new metabolites, purified from the gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from Junceella fragilis, Junceella gemmacea, Junceella juncea, and Junceella sp., collected from tropical Indo-Pacific Ocean. Some of these compounds exhibited potential biomedical activities.

Isolation and Structure Elucidation of Cembranoids from a Dongsha Atoll Soft Coral Sarcophyton stellatum.

Six new polyoxygenated cembrane-based diterpenoids, stellatumolides A⁻C (1⁻3), stellatumonins A and B (4 and 5), and stellatumonone (6), were isolated together with ten known related compounds (7⁻16) from the ethyl acetate (EtOAc) extract of soft coral Sarcophyton stellatum. The structures of the new compounds were established by extensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and data comparison with related structures. Compounds 8 and 14 were isolated from a natural source for the first time. The isolated metabolites were shown to be not cytotoxic against a limited panel of cancer cells. Compound 9 showed anti-inflammatory activity by reducing the expression of proinflammatory cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins in lipopolysaccharide (LPS)-stimulated mouse leukaemic monocyte macrophage (RAW 264.7) cells.

Study of the anti-allergic and anti-inflammatory activity of Brachychiton rupestris and Brachychiton discolor leaves (Malvaceae) using in vitro models.

BACKGROUND: Brachychiton rupestris and Brachychiton discolor (Malvaceae) are ornamental trees native to Australia. Some members of Brachychiton and its highly related genus, Sterculia, are employed in traditional medicine for itching, dermatitis and other skin diseases. However, scientific studies on these two genera are scarce. Aiming to reveal the scientific basis of the folk medicinal use of these plants, the cytotoxicity, anti-inflammatory and anti-allergic activities of Brachychiton rupestris and Brachychiton discolor leaves extracts and fractions were evaluated. Also, phytochemical investigation of B. rupestris was performed to identify the compounds exerting the biological effect. METHODS: Extracts as well as fractions of Brachychiton rupestris and Brachychiton discolor were tested for their cytotoxicity versus hepatoma HepG2, lung A549, and breast MDA-MB-231 cancer cell lines. Assessment of the anti-allergic activity was done using degranulation assay in RBL-2H3 mast cells. Anti-inflammatory effect was tested by measuring the suppression of superoxide anion production as well as elastase release in fMLF/CB-induced human neutrophils. Phytochemical investigation of the n-hexane, dichloromethane and ethyl acetate fractions of B. rupestris was done using different chromatographic and spectroscopic techniques. RESULTS: The tested samples showed no cytotoxicity towards the tested cell lines. The nonpolar fractions of both B. rupestris and B. discolor showed potent anti-allergic potency by inhibiting the release of ß-hexosaminidase. The dichloromethane fraction of both species exhibited the highest anti-inflammatory activity by suppressing superoxide anion generation and elastase release with IC50 values of 2.99 and 1.98 µg/mL, respectively for B. rupestris, and 0.78 and 1.57 µg/mL, respectively for B. discolor. Phytochemical investigation of various fractions of B. rupestris resulted in the isolation of ß-amyrin acetate (1), ß-sitosterol (2) and stigmasterol (3) from the n-hexane fraction. Scopoletin (4) and ß-sitosterol-3-O-ß-D-glucoside (5) were obtained from the dichloromethane fraction. Dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucoside (6) and dihydrodehydrodiconiferyl alcohol 9-O-ß-D-glucoside (7) were separated from the ethyl acetate fraction. Scopoletin (4) showed anti-allergic and anti-inflammatory activity. CONCLUSIONS: It was concluded that the nonpolar fractions of both Brachychiton species exhibited anti-allergic and anti-inflammatory activities.

4ß-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells.

Reactive oxygen species (ROS) induction had been previously reported in 4ß-hydroxywithanolide (4ßHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4ßHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4ßHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4ßHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4ßHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4ßHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4ßHWE-treated oral cancer cells than in oral normal cells. All the 4ßHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4ßHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells.