Identification of a Prenyl Chalcone as a Competitive Lipoxygenase Inhibitor: Screening, Biochemical Evaluation and Molecular Modeling Studies

Zeraik, Maria Luiza; Pauli, Ivaní; Dutra, Luiz Antônio; Cruz, Raquel S.; Valli, Marília; Paracatu, Luana Chiquetto; Faria, Carolina Maria Quinello Gomes de; Ximenes, Valdecir Farias; Regasini, Luis Octávio; Andricopulo, Adriano D.; Bolzani, Vanderlan S.

doi:10.3390/molecules26082205

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…The plant lipoxygenase pathway is in many aspects equivalent to the “arachidonic acid cascades” in animals . For this reason, the in vitro inhibition of lipoxygenase (LOX) constitutes a good model for the screening of plants with anti-inflammatory potential . LOXs are sensitive to antioxidants, and most of their action may consist of inhibition of lipid hydroperoxide formation due to scavenging of lipid peroxyl radicals formed in the course of enzyme peroxidation.…”

Section: Results and Discussionmentioning

confidence: 99%

“…65 For this reason, the in vitro inhibition of lipoxygenase (LOX) constitutes a good model for the screening of plants with anti-inflammatory potential. 66 LOXs are sensitive to antioxidants, and most of their action may consist of inhibition of lipid hydroperoxide formation due to scavenging of lipid peroxyl radicals formed in the course of enzyme peroxidation. From one study, it has been shown that ethyl acetate extract of the leaves and flowers of Mikania micrantha exhibited 98 and 185 μg/mL IC 50 , respectively.…”

Section: Resultsmentioning

confidence: 99%

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Green Synthesis of Gold Nano-bioconjugates from Onion Peel Extract and Evaluation of Their Antioxidant, Anti-inflammatory, and Cytotoxic Studies

2021

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Plant secondary metabolites such as flavonoids demonstrate high degrees of antioxidant, anti-inflammatory, and anticancer activities. Among flavonoids, quercetin plays an important role in inflammation by downregulating the level of various cytokines. Thereby, in this work, onion (Allium cepa) peel was successfully utilized for the synthesis of gold nano-bioconjugates acting as a natural therapeutic drug. In this process, crude onion peel extract was first divided into different fractionates, namely, ethyl acetate, butanol, methanol, and water, and they were subjected to various preliminary studies of antioxidant activities. The ethyl acetate fractionate shows high antioxidant activities in all the assays. The bioactive components were identified and found to contain a high amount of quercetin as confirmed by liquid chromatography with tandem mass spectrometry and high-performance liquid chromatogrpahy. Three gold nano-bioconjugates were prepared with different concentrations of the ethyl acetate fractionate. Various biochemical anti-inflammatory assays were carried out and compared with the active ethyl acetate fraction of the onion peel drug (OPD). The cytotoxicity of the nano-bioconjugate system and the OPD was checked in the myoblast L6 cell line from skeletal muscle tissues to evaluate the toxicity. All the three nano-bioconjugates A, B, and E demonstrated high percentages of cell viability, viz., 73.07, 72.3, and 69.15%, respectively, at their highest concentration of 200 μg/mL. The OPD also showed 88.56% cell viability with no toxic effects in the myoblast L6 cell line from skeletal muscle tissues. The reactive oxygen species reduction of nano-bioconjugate B showed a marked reduction of 76.77% at a maximum concentration of 200 μg/mL, whereas the OPD showed 68.17%. Hence, through this work, a cheap source of nano-bioconjugates is developed, which can act as a potent antioxidant and anti-inflammatory agent and are more active in comparison to the OPD alone.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Green Synthesis of Gold Nano-bioconjugates from Onion Peel Extract and Evaluation of Their Antioxidant, Anti-inflammatory, and Cytotoxic Studies

2021

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“…Another flavonoid subclass, chalcone, was tentatively identified (compound 3), sharing common fragments with compound 7, including m/z 323.1281, 255.0615 and 254.0567. Various pharmacological effects of the prenylated chalcones (e.g., compound 3) have been reported in the literature, including the anticancer activity [67][68][69][70][71]. Compounds 1 and 2 differ from previously isolated and fully characterised prenyl stilbenes such as compounds 4 and 5 in one extra oxygen atom (15.99-16.00 Da) and share their characteristic fragments at m/z 188.0480, and 144.0580.…”

Section: Biochemometric and Lcms Metabolomic Identification Of Cytotoxic Metabolites Of Ap-1mentioning

confidence: 99%

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

Alsherbiny

Bhuyan

Radwan

et al. 2021

IJMS

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The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy or reduce the side effects of standard chemotherapy. Doxorubicin (DOX), a standard drug for breast cancer, has several disadvantages, including severe side effects and the development of drug resistance. Recently, we reported the potential bioactive markers of Australian propolis extract (AP−1) and their broad spectrum of pharmacological activities. In the present study, we explored the synergistic interactions between AP−1 and DOX in the MCF7 breast adenocarcinoma cells using different synergy quantitation models. Biochemometric and metabolomics-driven analysis was performed to identify the potential anticancer metabolites in AP−1. The molecular mechanisms of synergy were studied by analysing the apoptotic profile via flow cytometry, apoptotic proteome array and measuring the oxidative status of the MCF7 cells treated with the most synergistic combination. Furthermore, label-free quantification proteomics analysis was performed to decipher the underlying synergistic mechanisms. Five prenylated stilbenes were identified as the key metabolites in the most active AP−1 fraction. Strong synergy was observed when AP−1 was combined with DOX in the ratio of 100:0.29 (w/w) as validated by different synergy quantitation models implemented. AP−1 significantly enhanced the inhibitory effect of DOX against MCF7 cell proliferation in a dose-dependent manner with significant inhibition of the reactive oxygen species (p < 0.0001) compared to DOX alone. AP−1 enabled the reversal of DOX-mediated necrosis to programmed cell death, which may be advantageous to decline DOX-related side effects. AP−1 also significantly enhanced the apoptotic effect of DOX after 24 h of treatment with significant upregulation of catalase, HTRA2/Omi, FADD together with DR5 and DR4 TRAIL-mediated apoptosis (p < 0.05), contributing to the antiproliferative activity of AP−1. Significant upregulation of pro-apoptotic p27, PON2 and catalase with downregulated anti-apoptotic XIAP, HSP60 and HIF-1α, and increased antioxidant proteins (catalase and PON2) may be associated with the improved apoptosis and oxidative status of the synergistic combination-treated MCF7 cells compared to the mono treatments. Shotgun proteomics identified 21 significantly dysregulated proteins in the synergistic combination-treated cells versus the mono treatments. These proteins were involved in the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and suppressed RIF1 encoded proteins. The overexpression of UPF2 was noticed in the synergistic combination treatment, which could assist in overcoming doxorubicin resistance-associated long non-coding RNA and metastasis of the MCF7 cells. In conclusion, we identified the significant synergy and highlighted the key molecular pathways in the interaction between AP−1 and DOX in the MCF7 cells together with the AP−1 anticancer metabolites. Further in vivo and clinical studies are warranted on this synergistic combination.

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“…Chalcones, , in particular, flavonoids, are natural products that display a broad spectrum of activities such as anticancer, antibacterial, antifungal, antimalarial, antidiabetic, anti-inflammatory, lipoxygenase inhibition, , and antioxidant . Representatives of this class of compounds are already used in clinical practice or are undergoing clinical trials, including metochalcone, sofalcone, isoliquiritigenin, xanthohumol, hesperidin, and methylchalcone. , …”

Section: Introductionmentioning

confidence: 99%

Thiocarbohydrazone and Chalcone-Derived 3,4-Dihydropyrimidinethione as Lipid Peroxidation and Soybean Lipoxygenase Inhibitors

et al. 2023

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The potential of the 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione (abbreviated as KKII5) and (E)-N′-benzylidenehydrazinecarbothiohydrazide (abbreviated as DKI5) compounds as possible drug leads is investigated. KKII5 and DKI5 are synthesized in high yield of up to 97%. Their structure, binding in the active site of the LOX-1 enzyme, and their toxicity are studied via joint experimental and computational methodologies. Specifically, the structure assignment and conformational analysis were achieved by applying homonuclear and heteronuclear 2D nuclear magnetic resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and density functional theory (DFT). The obtained DFT lowest energy conformers were in agreement with the NOE correlations observed in the 2D-NOESY spectra. Additionally, docking and molecular dynamics simulations were performed to discover their ability to bind and remain stabile in the active site of the LOX-1 enzyme. These in silico experiments and DFT calculations indicated favorable binding for the enzyme under study. The strongest binding energy, −9.60 kcal/mol, was observed for dihydropyrimidinethione KKII5 in the active site of LOX-1. ADMET calculations showed that the two molecules lack major toxicities and could serve as possible drug leads. The redox potential of the active center of LOX-1 with the binding molecules was calculated via DFT methodology. The results showed a significantly smaller energy attachment of 2.8 eV with KKII5 binding in comparison to DKI5. Thus, KKII5 enhanced the ability of the active center to receive electrons compared to DKI5. This is related to the stronger binding interaction of KKII5 relative to that of DK15 to LOX-1. The two very potent LOX-1 inhibitors exerted IC50 19 μΜ (KKII5) and 22.5 μΜ (DKI5). Furthermore, they both strongly inhibit lipid peroxidation, namely, 98% for KKII5 and 94% for DKI5.

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Identification of a Prenyl Chalcone as a Competitive Lipoxygenase Inhibitor: Screening, Biochemical Evaluation and Molecular Modeling Studies

Cited by 10 publications

References 33 publications

Green Synthesis of Gold Nano-bioconjugates from Onion Peel Extract and Evaluation of Their Antioxidant, Anti-inflammatory, and Cytotoxic Studies

Green Synthesis of Gold Nano-bioconjugates from Onion Peel Extract and Evaluation of Their Antioxidant, Anti-inflammatory, and Cytotoxic Studies

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

Thiocarbohydrazone and Chalcone-Derived 3,4-Dihydropyrimidinethione as Lipid Peroxidation and Soybean Lipoxygenase Inhibitors

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