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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
2.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360846

RESUMO

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.


Assuntos
Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Furanos/farmacologia , Fenantrenos/farmacologia , Quinonas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Paclitaxel/farmacologia
3.
Phytochemistry ; 191: 112902, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34384921

RESUMO

Thirteen undescribed diterpenoid quinones were isolated from the dried roots of Salvia miltiorrhiza. Their structures were determined by extensive analysis, including NMR, HRESIMS, and IR. Their absolute configurations were determined by X-ray diffraction, calculated and experimental circular dichroism spectroscopy, and optical rotation. In the evaluation of bioactivities, salviadionether obviously inhibited the proliferation of HCT-116 cells. R-(+)-salmiltiorin E and R-(+)-grandifolia D both showed inhibitory activities on a variety of tumor cells. Salvianone ester A showed strong cytotoxicity to tumor-repopulating cells (TRCs) with an IC50 value of 2.19 µM.


Assuntos
Diterpenos , Salvia miltiorrhiza , Salvia , Diterpenos/farmacologia , Estrutura Molecular , Raízes de Plantas , Quinonas/farmacologia , Rizoma
4.
Phytomedicine ; 91: 153694, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34403879

RESUMO

BACKGROUND: Atherosclerosis is a chronic vascular inflammatory disease with complex pathogenesis. Its serious consequence is insufficient blood supply to heart and brain, which eventually leads to myocardial ischemia, infarction and stroke. Hydroxysafflor yellow A (HSYA), a single chalcone glycoside compound with a variety of pharmacological effects, which has shown a potential biological activity for prevention and treatment of atherosclerosis. PURPOSE: The main purpose of this review is to comprehensively elucidate the mechanism of HSYA on atherosclerosis and its risk factors (hyperlipidemia, hypertension and diabetes mellitus). METHOD: The literatures on HSYA in the treatment of atherosclerosis and its risk factors were searched in PubMed, Google Scholar, China National Knowledge Infrastructure, including in vitro (cell), in vivo (animal) and clinical (human) studies, and summarized reasonably. RESULTS: HSYA is a promising natural product for treating atherosclerosis. It can suppress foam cell formation, vascular endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, and platelet activation. The mechanisms are achieved by regulating the reverse cholesterol transport process, fatty acid synthesis, oxidative stress, PI3K/Akt/mTOR, NLRP3 inflammasome, TNFR1/NF-κB, NO-cGMP, Bax/Bcl-2, MAPKs, CDK/CyclinD and TLR4/Rac1/Akt signaling pathways. Besides, HSYA is devoted to lowering blood lipids, regulating ion channels, reducing vascular inflammation, and protecting pancreatic beta cells, which is conducive to reducing the harm of independent risk factors of atherosclerosis. CONCLUSIONS: HSYA exhibits the preventive and therapeutic effects on atherosclerosis and its risk factors in vivo and in vitro, which is relevant to multiple mechanisms. The clinical trials of HSYA need to be further investigated to provide a solid foundation for its clinical application.


Assuntos
Aterosclerose , Carthamus tinctorius , Chalcona , Quinonas , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Carthamus tinctorius/química , Chalcona/análogos & derivados , Chalcona/farmacologia , Humanos , Compostos Fitoquímicos/farmacologia , Quinonas/farmacologia
5.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443298

RESUMO

Naphthodianthrones such as fagopyrin and hypericin found mainly in buckwheat (Fagopyrum spp.) and St. John's wort (SJW) (Hypericum perforatum L.) are natural photosensitizers inside the cell. The effect of photosensitizers was studied under dark conditions on growth, morphogenesis and induction of death in Saccharomyces cerevisiae. Fagopyrin and hypericin induced a biphasic and triphasic dose response in cellular growth, respectively, over a 10-fold concentration change. In fagopyrin-treated cells, disruptions in the normal cell cycle progression were evident by microscopy. DAPI staining revealed several cells that underwent premature mitosis without budding, a striking morphological abnormality. Flow Cytometric (FC) analysis using a concentration of 100 µM showed reduced cell viability by 41% in fagopyrin-treated cells and by 15% in hypericin-treated cells. FC revealed the development of a secondary population of G1 cells in photosensitizer-treated cultures characterized by small size and dense structures. Further, we show that fagopyrin and the closely related hypericin altered the shape and the associated fluorescence of biofilm-like structures. Colonies grown on solid medium containing photosensitizer had restricted growth, while cell-to-cell adherence within the colony was also affected. In conclusion, the photosensitizers under dark conditions affected culture growth, caused toxicity, and disrupted multicellular growth, albeit with different efficiencies.


Assuntos
Antracenos/farmacologia , Corantes/farmacologia , Perileno/análogos & derivados , Fármacos Fotossensibilizantes/farmacologia , Plâncton/crescimento & desenvolvimento , Quinonas/farmacologia , Saccharomycetales/crescimento & desenvolvimento , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fluorescência , Morfogênese/efeitos dos fármacos , Perileno/farmacologia , Plâncton/efeitos dos fármacos , Saccharomycetales/citologia , Saccharomycetales/efeitos dos fármacos
6.
Biomed Pharmacother ; 139: 111674, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243610

RESUMO

OBJECTIVES: In calcific aortic valve disease (CAVD), the valve interstitial cells (VIC) osteogenic phenotype changes can lead to thickening and calcification of the valve leaflets,eventually lead to restricted valve movement and life-threatening. This study aims to investigate the effect and mechanism of dihydrotanshinone I (DHI) on osteogenic medium (OM) induced osteogenic phenotypic transition of porcine valve interstitial cells (PVICs), which can provide theoretical and scientific basis for clinical intervention in CAVD. METHODS AND RESULTS: Immunohistochemical methods were used to detect the expression of osteogenic indicators Runx2, OPN and inflammation indicators IL-1ß and p-NF-κB in valve specimens of CAVD patients(N = 3) and normal controls(N = 1). PVICs stimulated by osteoblastic medium (OM) were treated with or without DHI. CCK8, ALP and Alizarin Red S staining were used to detect cell growth and calcification, respectively. The results showed that under the treated with DHI, compared with OM, the formation of calcium nodules was reduced, and the expression of calcification-related markers Runx2 and OPN were down-regulated, which quantified by qRT-PCR and western blot. In addition, on the basis of OM induction, DHI also inhibited the phosphorylation of the NF-κB/ERK1/2 and SMAD1/5/8 signaling pathway. CONCLUSION: DHI (10 µM) treatment can reverse the osteogenic phenotypic transition of PVICs induced by osteogenic medium, and the mechanism may be related to NF-κB、ERK 1/2 and Smad1/5/8 pathways.


Assuntos
Estenose da Valva Aórtica/tratamento farmacológico , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Calcinose/tratamento farmacológico , Furanos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fenantrenos/farmacologia , Quinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Calcinose/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Suínos
7.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201389

RESUMO

The objective of this study was to determine reactive oxygen species (ROS) produced by fagopyrin F-rich fraction (FFF) separated from Tartary buckwheat flower extract exposed to lights and to investigate its antibacterial photodynamic inactivation (PDI) against Streptococcus mutans and its biofilm. ROS producing mechanisms involving FFF with light exposure were determined using a spectrophotometer and a fluorometer. S. mutans and its biofilm inactivation after PDI treatment of FFF using blue light (BL; 450 nm) were determined by plate count method and crystal violet assay, respectively. The biofilm destruction by ROS produced from FFF after exposure to BL was visualized using confocal laser scanning microscopy (CLSM) and field emission scanning electron microscope (FE-SEM). BL among 3 light sources produced type 1 ROS the most when applying FFF as a photosensitizer. FFF exposed to BL (5 and 10 J/cm2) significantly more inhibited S. mutans viability and biofilm formation than FFF without the light exposure (p < 0.05). In the PDI of FFF exposed to BL (10 J/cm2), an apparent destruction of S. mutans and its biofilm were observed by the CLSM and FE-SEM. Antibacterial PDI effect of FFF was determined for the first time in this study.


Assuntos
Biofilmes/crescimento & desenvolvimento , Fagopyrum/química , Flores/química , Fármacos Fotossensibilizantes/farmacologia , Extratos Vegetais/farmacologia , Quinonas/farmacologia , Streptococcus mutans/crescimento & desenvolvimento , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Luz , Fotoquimioterapia , Streptococcus mutans/efeitos dos fármacos
8.
Int J Biochem Cell Biol ; 137: 106033, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34216755

RESUMO

In clinical treatment, there is increasingly prevalent that traditional Chinese medicine treats common bone diseases including osteoporosis. Hydroxysafflor yellow A (HSYA), one of the essential compounds of Safflower, has been used as the therapy for thrombus, myocardial ischemia, and inflammation, but its effect on osteogenesis through epigenetic control and ovariectomy-induced bone loss in vivo has not been explored. Therefore, the study aimed to explore the function and mechanism of HSYA on bone formation and development. We found HSYA could enhance the cell viability and promote osteogenesis of hBMSCs in vitro. Mechanistically, HSYA could increase the expression of ß-catenin leading to its accumulation in the nucleus and activation of downstream targets to promote osteogenesis. Besides, RNA-seq and quantitative RT-PCR and western blot showed KDM7A was significantly increased by HSYA. The occupancy of H3K27me2 on ß-catenin promoter was significantly decreased by HSYA, which could be reversed by silencing endogenous KDM7A. More importantly, HSYA promoted bone development in chick embryos and prevented ovariectomy (OVX)-induced bone loss in SD rats. Taken together, our study has shown convincing evidence that HSYA could promote osteogenesis and bone development via epigenetically regulating ß-catenin and prevent ovariectomy-induced bone loss.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Chalcona/análogos & derivados , Osteogênese , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Quinonas/farmacologia , beta Catenina/metabolismo , Animais , Proliferação de Células , Chalcona/farmacologia , Feminino , Osteoporose/etiologia , Osteoporose/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , beta Catenina/genética
9.
Biochem J ; 478(13): 2517-2531, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34198325

RESUMO

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.


Assuntos
Antivirais/química , Antivirais/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Compostos de Anilina/farmacologia , Animais , Benzamidas/farmacologia , Chlorocebus aethiops , Proteases Semelhantes à Papaína de Coronavírus/genética , Proteases Semelhantes à Papaína de Coronavírus/isolamento & purificação , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Sinergismo Farmacológico , Ensaios Enzimáticos , Flavinas/farmacologia , Transferência Ressonante de Energia de Fluorescência , Furanos/farmacologia , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Naftalenos/farmacologia , Fenantrenos/farmacologia , Quinonas/farmacologia , Reprodutibilidade dos Testes , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/química , Células Vero , Replicação Viral/efeitos dos fármacos
10.
Eur J Med Chem ; 223: 113632, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34153576

RESUMO

Privileged structures are conductive to discover novel bioactive substances because they can bind to multiple targets with high affinity. Quinones are considered to be a privileged structure and useful template for the design of new compounds with potential pharmacological activity. This article presents the recent developments (2014-2021 update) of quinones in the fields of antitumor, antibacterial, antifungal, antiviral, anti-Alzheimer's disease (AD) and antimalarial, mainly focusing on biological activities, structural modification and mechanism of action.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Nootrópicos/farmacologia , Quinonas/farmacologia , Animais , Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Doenças Transmissíveis/tratamento farmacológico , Desenho de Fármacos , Descoberta de Drogas , Humanos , Neoplasias/tratamento farmacológico , Nootrópicos/síntese química , Quinonas/síntese química
11.
Phytomedicine ; 87: 153579, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33991865

RESUMO

BACKGROUND: Hydroxysafflor yellow A (HSYA) from the flower of Carthamus tinctorius (Safflower) has been reported to have various pharmacological effects. However, little is known about the bioactivities of other chemical constituents in Safflower and the relationship between enhancement of blood circulation and hepatoprotection by HSYA. PURPOSE: The present research was to evaluate the antithrombotic and hepatoprotective activities of HSYA and C, examine their mechanisms of actions, including influence on the excretion velocity of acetaminophen, and the relationship between the antithrombotic, hepatoprotective, and other bioactivities. METHODS: The hepatoprotective activities were examined by acetaminophen (APAP)-induced zebrafish toxicity and carbon tetrachloride (CCl4)-induced mouse liver injury. The concentrations of APAP in zebrafish and APAP that was excreted to the culture media were quantified by UHPLC-MS. The anti-thrombosis effect of HSYA and C were examined by the phenylhydrazine (PHZ)-induced zebrafish thrombosis. RESULTS: HSYA and HSYC showed robust protection on APAP-induced toxicity and PHZ-induced thrombosis. The hepatoprotective effects of HSYA and C were more potent than that of the positive control, acetylcysteine (61.7% and 58.0%, respectively, vs. 56.9% at 100 µM) and their antithrombosis effects were more robust than aspirin (95.1% and 86.2% vs. 52.7% at 100 µM). HSYA and C enhanced blood circulation, rescued APAP-treated zebrafish from morphological abnormalities, and mitigated APAP-induced toxicity in liver development in liver-specific RFP-expressing transgenic zebrafish. HSYC attenuated CCl4-induced mouse liver injury and regulated the levels of HIF-1α, iNOS, TNF-α, α-SMA, and NFκB in liver tissues. HSYA was also protective in a dual thrombotic and liver toxicity zebrafish model. By UHPLC-MS, HSYA accelerated the excretion of APAP. CONCLUSION: HSYA and C are the bioactive constituents of Safflower that are responsible for the herbal drug's traditional use in promoting blood circulation to remove blood stasis. Safflower and its chalcone constituents may protect from damage due to exogenous or disease-induced endogenous toxins by enhancing the excretion velocity of toxins.


Assuntos
Acetaminofen/toxicidade , Chalcona/análogos & derivados , Fibrinolíticos/farmacologia , Substâncias Protetoras/farmacologia , Quinonas/farmacologia , Acetaminofen/farmacocinética , Animais , Animais Geneticamente Modificados , Circulação Sanguínea/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Carthamus tinctorius/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Chalconas/isolamento & purificação , Chalconas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos ICR , Fenil-Hidrazinas/toxicidade , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Quinonas/isolamento & purificação , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Peixe-Zebra/genética
13.
Chem Asian J ; 16(10): 1221-1224, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33881805

RESUMO

Peroxalate CL as an energy source to excite photosensitizers has attracted tremendous attention in photodynamic therapy (PDT). In this work, peroxyoxalate CPPO and hypocrellin B (HB)-based nanoparticles (CBNPs) for ultrasound (US)-enhanced self-exciting PDT were designed and prepared. CBNPs showed an excellent therapeutic effect against cancer cells with the assistance of US. This US-enhanced-chemiluminescence system avoids the dependence on external light and provides an example for inspiring more effective and precise strategies for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Estruturas Metalorgânicas/farmacologia , Perileno/análogos & derivados , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Quinonas/farmacologia , Ondas Ultrassônicas , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Modelos Moleculares , Tamanho da Partícula , Perileno/química , Perileno/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Quinonas/química
14.
Bioorg Med Chem Lett ; 41: 127998, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794318

RESUMO

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.


Assuntos
Alcaloides/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Pirróis/farmacologia , Quinonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
15.
Bioorg Chem ; 111: 104823, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798844

RESUMO

Herein, the design and synthesis of new 2-phenyl(pyridinyl)benzimidazolequinones and their 5-phenoxy derivatives as potential anti-Trypanosoma cruzi agents are described. The compounds were evaluated in vitro against the epimastigotes and trypomastigote forms of Trypanosoma cruzi. The replacing of a benzene moiety in the naphthoquinone system by an imidazole enhanced the trypanosomicidal activity against Trypanosoma cruzi. Three of the tested compounds (11a-c) showed potent trypanosomicidal activity and compound 11a, with IC50 of 0.65 µM on the trypomastigote form of T. cruzi, proved to be 15 times more active than nifurtimox. Additionally, molecular docking studies indicate that the quinone derivatives 11a-c could have a multitarget profile interacting preferentially with trypanothione reductase and Old Yellow Enzyme.


Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Quinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
16.
Molecules ; 26(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806577

RESUMO

Short-chain quinones (SCQs) have been investigated as potential therapeutic candidates against mitochondrial dysfunction, which was largely thought to be associated with the reversible redox characteristics of their active quinone core. We recently reported a library of SCQs, some of which showed potent cytoprotective activity against the mitochondrial complex I inhibitor rotenone in the human hepatocarcinoma cell line HepG2. To better characterize the cytoprotection of SCQs at a molecular level, a bioactivity profile for 103 SCQs with different compound chemistries was generated that included metabolism related markers, redox activity, expression of cytoprotective proteins and oxidative damage. Of all the tested endpoints, a positive correlation with cytoprotection by SCQs in the presence of rotenone was only observed for the NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent reduction of SCQs, which also correlated with an acute rescue of ATP levels. The results of this study suggest an unexpected mode of action for SCQs that appears to involve a modification of NQO1-dependent signaling rather than a protective effect by the reduced quinone itself. This finding presents a new selection strategy to identify and develop the most promising compounds towards their clinical use.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Trifosfato de Adenosina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Citoproteção , Ácido Láctico/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Quinonas/farmacologia , Apoptose , Proliferação de Células , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredução , Estresse Oxidativo , Transdução de Sinais , Células Tumorais Cultivadas
17.
Mar Drugs ; 19(5)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925873

RESUMO

In this study, the anti-proliferative effect of ilimaquinone, a sesquiterpene derivative from the marine sponge, in breast cancer cells was investigated. Ilimaquinone inhibited the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 10.6 µM and 13.5 µM, respectively. Non-tumorigenic human breast epithelial cells were less sensitive to ilimaquinone than breast cancer cells. Flow cytometric and Western blot analysis showed that ilimaquinone induced S-phase arrest by modulating the expression of p-CDC-2 and p21. Ilimaquinone induces apoptosis, which is accompanied by multiple biological biomarkers, including the downregulation of Akt, ERK, and Bax, upregulation of p38, loss of mitochondrial membrane potential, increased reactive oxygen species generation, and induced autophagy. Collectively, these findings suggest that ilimaquinone causes cell cycle arrest as well as induces apoptosis and autophagy in breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Poríferos/metabolismo , Quinonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinonas/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Sesquiterpenos/isolamento & purificação , Transdução de Sinais
18.
Phytomedicine ; 85: 153532, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33735723

RESUMO

BACKGROUND: Mitochondria are key cellular organelles that are essential for cell fate decisions. Hydroxysafflor yellow A (HSYA) has displayed an impressively essential role in protection of cerebral ischemia/reperfusion (I/R). However, the mitochondrial effect of HSYA on Brain Microvascular Endothelial Cells (BMECs) under I/R remains to be largely unclear. PURPOSE: To evaluate the protective effects of HSYA-mediated mitochondrial permeability transition pore (mPTP) on cerebral I/R injury and its mechanism. METHODS: Cerebral I/R injury was established by the model of Middle cerebral artery occlusion (MCAO) in rats. Furthermore, to further clarify the relevant mechanism of HSYA's effects on mPTP, inhibition of extracellular regulated protein kinases (ERK) with U0126 and transfect with Cyclophilin D (CypD) SiRNA to reversely verified whether the protective effects of HSYA were exerted by regulating the Mitogen-activated protein kinase kinase (MEK)/ERK/CypD pathway. RESULTS: HSYA treatment significantly increased BMECs viability, decreased the generation of ROS, opening of mPTP and translocation of cytochrome c after OGD/R. In addition to inhibited CypD, HSYA potentiated MEK and increased phosphorylation of ERK expression in BMECs, inhibited apoptosis mediated by mitochondrial. Notably, HSYA also significantly ameliorated neurological deficits and decreased the infarct volume in rats. CONCLUSION: HSYA reduced the CytC export from mitochondrial by inhibited the open of mPTP via MEK/ERK/CypD pathway, contributing to the protection of I/R. Thus, our study not only revealed novel mechanisms of HSYA for its anti-I/R function, but also provided a template for the design of novel mPTP inhibitor for the treatment of various mPTP-related diseases.


Assuntos
Apoptose/efeitos dos fármacos , Chalcona/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial , Quinonas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Isquemia Encefálica/tratamento farmacológico , Chalcona/farmacologia , Células Endoteliais/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Mitocôndrias/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley
19.
J Nat Prod ; 84(2): 436-443, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33560122

RESUMO

A new axial chiral binaphtoquinone, hypocrellone (1), and a new perylenequinone, hypomycin F (2), were isolated from the stromata of Hypocrella bambusae, together with five known compounds, 3-7. The structures of 1 and 2 were assigned by spectroscopic and HRESIMS data analyses. The axial chirality of 1 was determined by electronic circular dichroism data analysis, and the absolute configurations of 2 and 3 were determined by X-ray crystallography. The axial chirality of 7 was determined by UV-induced photooxidation from 4. Compounds 1, 4, and 5 showed inhibitory activity against pseudotyped SARS-CoV-2 infection in 293T-ACE2 cells with IC50 values of 0.17, 0.038, and 0.12 µM. Compounds 4 and 5 were also active against live SARS-CoV-2 infection with EC50 values of 0.22 and 0.21 µM, respectively. Further cell-cell fusion assays, surface plasmon resonance assays, and molecular docking studies revealed that 4 and 5 could bind with the receptor-binding domain of SARS-CoV-2 S protein to prevent its interaction with human angiotensin-converting enzyme II receptor. Our results revealed that 4 and 5 are potential SARS-CoV-2 entry inhibitors.


Assuntos
Hypocreales/química , Naftoquinonas/farmacologia , Perileno/análogos & derivados , Quinonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Naftoquinonas/química , Perileno/química , Perileno/farmacologia , Quinonas/química , SARS-CoV-2/fisiologia
20.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478045

RESUMO

We have shown that autoxidized polyphenolic nutraceuticals oxidize H2S to polysulfides and thiosulfate and this may convey their cytoprotective effects. Polyphenol reactivity is largely attributed to the B ring, which is usually a form of hydroxyquinone (HQ). Here, we examine the effects of HQs on sulfur metabolism using H2S- and polysulfide-specific fluorophores (AzMC and SSP4, respectively) and thiosulfate sensitive silver nanoparticles (AgNP). In buffer, 1,4-dihydroxybenzene (1,4-DB), 1,4-benzoquinone (1,4-BQ), pyrogallol (PG) and gallic acid (GA) oxidized H2S to polysulfides and thiosulfate, whereas 1,2-DB, 1,3-DB, 1,2-dihydroxy,3,4-benzoquinone and shikimic acid did not. In addition, 1,4-DB, 1,4-BQ, PG and GA also increased polysulfide production in HEK293 cells. In buffer, H2S oxidation by 1,4-DB was oxygen-dependent, partially inhibited by tempol and trolox, and absorbance spectra were consistent with redox cycling between HQ autoxidation and H2S-mediated reduction. Neither 1,2-DB, 1,3-DB, 1,4-DB nor 1,4-BQ reduced polysulfides to H2S in either 21% or 0% oxygen. Epinephrine and norepinephrine also oxidized H2S to polysulfides and thiosulfate; dopamine and tyrosine were ineffective. Polyphenones were also examined, but only 2,5-dihydroxy- and 2,3,4-trihydroxybenzophenones oxidized H2S. These results show that H2S is readily oxidized by specific hydroxyquinones and quinones, most likely through the formation of a semiquinone radical intermediate derived from either reaction of oxygen with the reduced quinones, or from direct reaction between H2S and quinones. We propose that polysulfide production by these reactions contributes to the health-promoting benefits of polyphenolic nutraceuticals.


Assuntos
Citoproteção/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Quinonas/farmacologia , Antioxidantes/farmacologia , Células HEK293 , Humanos , Sulfeto de Hidrogênio/efeitos adversos , Oxirredução/efeitos dos fármacos , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo
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