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1.
Dalton Trans ; 50(35): 12226-12233, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34396374

RESUMO

Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC50, for SC2Mpro in the 8-34 µM range, the IC50 values are ca. 100 nM for Zn(NO3)2 which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)2 binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)+ to basic active site residues.


Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Tropolona/farmacologia , Zinco/farmacologia , Antivirais/química , Antivirais/farmacologia , COVID-19/virologia , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , SARS-CoV-2/enzimologia , Tropolona/análogos & derivados , Zinco/química
2.
J Nat Prod ; 84(7): 2020-2027, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34236881

RESUMO

The tropolone-bearing sesquiterpenes juniperone A (1) and norjuniperone A (2) were isolated from the folk medicinal plant Juniperus chinensis, and their structures were determined by a combination of spectroscopic and crystallographic methods. Photojuniperones A1 (3) and A2 (4), bearing bicyclo[3,2,0]heptadienones derived from tropolone, were photochemically produced and structurally identified by spectroscopic methods. Predicted by the machine learning-based assay, 1 significantly inhibited the action of tyrosinase. The new compounds also inhibited lipid accumulation and enhanced the extracellular glycerol excretion.


Assuntos
Juniperus/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Sesquiterpenos/farmacologia , Tropolona/farmacologia , Animais , Células Hep G2 , Humanos , Melanócitos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Fotoquímica , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , República da Coreia , Sesquiterpenos/isolamento & purificação , Tropolona/isolamento & purificação , Madeira/química
3.
Fitoterapia ; 146: 104733, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32979464

RESUMO

Chenopodium album Linn is used as the traditional Chinese medicine for treating cough, anorexia, piles, dysentery, diarrhea, and kills small worms in China. Nine new tropolones (1-9), and fourteen known tropolone derivatives (10-23) were elucidated by comprehensive spectroscopic data analysis and references from C. album Linn for the first time. Compounds (1-4) and compounds (13-14) displayed notably hepatoprotective activities in intro for lowering AST levels (19.63 ± 2.34 to 29.87 ± 1.27 U•L-1) and ALT levels (15.21 ± 1.18 to 20.29 ± 2.11 U•L-1) in HepG2 cells treated with H2O2. Compounds (8-9) and compounds (15-17) exhibited moderate antiproliferative activities in vitro against the human tumor cell lines with IC50 values ranging from 0.5 ± 0.2 to 15.5 ± 2.7 µM. A preliminary structure activity relationship was summarized and discussed scientifically, which provided new clues to design novel hepatoprotective and antiproliferative drugs based on the tropolone derivatives.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chenopodium album/química , Substâncias Protetoras/farmacologia , Tropolona/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , China , Medicamentos de Ervas Chinesas , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Substâncias Protetoras/isolamento & purificação , Relação Estrutura-Atividade , Tropolona/isolamento & purificação
4.
Mater Sci Eng C Mater Biol Appl ; 105: 110074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546393

RESUMO

Hydrogel membranes are often used as physical barriers in oral tissue reconstruction and facial surgery to isolate connective and epithelial tissues and form a closed space for undisturbed bone healing. In this study, gelatin and hyaluronic acid were crosslinked with genipin and loaded with a hinokitiol additive as a bacteriostatic agent for potential applications as regeneration membranes. This bifunctional membrane had biocompatibility and antibacterial activities on each membrane side for proper biodegradation. Different membrane groups of gelatin/hyaluronic acid were obtained via a solution casting technique and were genipin crosslinked. The membrane groups were further loaded with adequate hinokitiol at a loading concentration of up to 0.16 g/L (hinokitiol to phosphate buffered saline). Fourier transform infrared spectroscopy showed that gelatin and hyaluronic acid were crosslinked with genipin through cross-linking amide bond (CONH) formation with a cross-linking degree of over 84%. The groups with hinokitiol showed substantial antibacterial activity. Meanwhile, the addition of hinokitiol on hydrogel membranes did not significantly affect the tensile strength. However, it decreased the solubility of the membranes by slowing down the relaxation and degradation of their molecular junctions as hinokitiol is a hydrophobic compound with low permeability. Consequently, the degradation of hydrogel membranes with hinokitiol was delayed. In vitro cytocompatibility indicated that the cell viability of the groups with hinokitiol increased with incubation time, demonstrating that cell viability and proliferation were not affected by cell culture testing.


Assuntos
Antibacterianos , Hidrogéis , Teste de Materiais , Membranas Artificiais , Monoterpenos , Tropolona/análogos & derivados , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Reagentes de Ligações Cruzadas/química , Avaliação Pré-Clínica de Medicamentos , Gelatina/química , Ácido Hialurônico/química , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Iridoides/química , Camundongos , Monoterpenos/química , Monoterpenos/farmacocinética , Monoterpenos/farmacologia , Células NIH 3T3 , Tropolona/química , Tropolona/farmacocinética , Tropolona/farmacologia
5.
Biochemistry ; 58(9): 1188-1197, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714720

RESUMO

Enolase is a glycolytic metalloenzyme involved in carbon metabolism. The advantage of targeting enolase lies in its essentiality in many biological processes such as cell wall formation and RNA turnover and as a plasminogen receptor. We initially used a DARTS assay to identify enolase as a target in Escherichia coli. The antibacterial activities of α-, ß-, and γ-substituted seven-member ring tropolones were first evaluated against four strains representing a range of Gram-negative bacteria. We observed that the chemical properties and position of the substituents on the tropolone ring play an important role in the biological activity of the investigated compounds. Both α- and ß-substituted phenyl derivatives of tropolone were the most active with minimum inhibitory concentrations in the range of 11-14 µg/mL. The potential inhibitory activity of the synthetic tropolones was further evaluated using an enolase inhibition assay, X-ray crystallography, and molecular docking simulations. The catalytic activity of enolase was effectively inhibited by both the naturally occurring ß-thujaplicin and the α- and ß-substituted phenyl derivatives of tropolones with IC50 values in range of 8-11 µM. Ligand binding parameters were assessed by isothermal titration calorimetry and differential scanning calorimetry techniques and agreed with the in vitro data. Our studies validate the antibacterial potential of tropolones with careful consideration of the position and character of chelating moieties for stronger interaction with metal ions and residues in the enolase active site.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Fosfopiruvato Hidratase/antagonistas & inibidores , Tropolona/farmacologia , Antibacterianos/química , Calorimetria , Domínio Catalítico , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Bactérias Gram-Negativas/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Fosfopiruvato Hidratase/química , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , Tropolona/química
6.
Leuk Res ; 77: 17-27, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30612055

RESUMO

Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that are of interest due to their cytotoxic properties. MO-OH-Nap is a novel α-substituted tropolone that induces caspase cleavage and upregulates markers associated with the unfolded protein response (UPR) in multiple myeloma (MM) cells. Given previous reports that tropolones may function as iron chelators, we investigated the effects of MO-OH-Nap, as well as the known iron chelator deferoxamine (DFO), in MM cells in the presence or absence of supplemental iron. The ability of MO-OH-Nap to induce apoptosis and upregulate markers of the UPR could be completely prevented by co-incubation with either ferric chloride or ammonium ferrous sulfate. Iron also completely prevented the decrease in BrdU incorporation induced by either DFO or MO-OH-Nap. Ferrozine assays demonstrated that MO-OH-Nap directly chelates iron. Furthermore, MO-OH-Nap upregulates cell surface expression and mRNA levels of transferrin receptor. In vivo studies demonstrate increased Prussian blue staining in hepatosplenic macrophages in MO-OH-Nap-treated mice. These studies demonstrate that MO-OH-Nap-induced cytotoxic effects in MM cells are dependent on the tropolone's ability to alter cellular iron availability and establish new connections between iron homeostasis and the UPR in MM.


Assuntos
Apoptose/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Mieloma Múltiplo/patologia , Receptores da Transferrina/metabolismo , Tropolona/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cloretos/farmacologia , Desferroxamina/farmacologia , Feminino , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Compostos de Amônio Quaternário/farmacologia , Sideróforos/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Fitoterapia ; 132: 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30439445

RESUMO

The methanol extract of Olax imbricata roots afforded one new sesquiterpenoid tropolone and three new 1,2,3,4-tetrahydronaphthalene derivatives, olaximbrisides A-D (1-4). Their structures were determined by 1D and 2D NMR experiments in combination of HRESIMS. The relative configurations were assigned by the NOESY experiments. The absolute configurations were established by a combination of X-ray diffraction analysis and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for their cytotoxic effects against some cancer cell lines. Among them, compound 1 exhibited the cytotoxicities against MCF-7, HepG2 and LU cell lines with IC50 values of 16.3, 34.3 and 8.0 µM, respectively.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Olacaceae/química , Tetra-Hidronaftalenos/isolamento & purificação , Tropolona/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Raízes de Plantas/química , Tetra-Hidronaftalenos/farmacologia , Tropolona/farmacologia , Vietnã
8.
DNA Repair (Amst) ; 60: 89-101, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29112893

RESUMO

Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was ß-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that ß-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that ß-thujaplicin can radiosensitize cancer cells. Additionally, ß-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound ß-thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high-throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy.


Assuntos
Monoterpenos/uso terapêutico , Neoplasias/tratamento farmacológico , Rad51 Recombinase/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Tropolona/análogos & derivados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cupressaceae/química , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Quimioterapia Combinada , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Monoterpenos/farmacologia , Monoterpenos/toxicidade , Neoplasias/enzimologia , Neoplasias/genética , Extratos Vegetais , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Rad51 Recombinase/metabolismo , Radiossensibilizantes/farmacologia , Radiossensibilizantes/toxicidade , Tropolona/farmacologia , Tropolona/uso terapêutico , Tropolona/toxicidade
10.
Am J Chin Med ; 40(2): 387-98, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22419431

RESUMO

Solar UV radiation damages human skin by affecting skin tone and resiliency and leads to premature aging (photoaging). The skin damage is caused by the activation of the AP-1 transcription factor, which increases matrix metalloproteinase (MMP) expression and collagen degradation. An increase of interleukin (IL)-6 is also correlated with the activation of MMP-1 expression. ß-thujaplicin has shown both acaricidal and antimicrobial activities. Also, ß-thujaplicin has been shown to be protective against apoptosis due to the oxidative effects of UV irradiation. However, the effect of ß-thujaplicin on UVB-induced MMPs had not been investigated. In this study, after UVB exposure, MMP-1 and IL-6 production in human skin fibroblasts was examined in the presence of ß-thujaplicin, vitamin C, and vitamin E. The expression of MMP-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP-1, TIMP-3) and procollagen mRNA was also investigated. Results showed that UVB-induced MMP-1 production was suppressed by the ß-thujaplicin treatment in a dose-dependent manner, but not by vitamin C and vitamin E. ß-thujaplicin also prevented the up-regulation of MMP-1 and MMP-3 mRNA. Moreover, the UVB-suppressed procollagen gene expression was restored to normal by ß-thujaplicin. Neither UVB nor ß-thujaplicin affected the mRNA expression of TIMP-1 and TIMP-3. The IL-6 production induced by UVB was lower in ß-thujaplicin treated fibroblasts than in the controls. In conclusion, this study shows the capability of ß-thujaplicin in preventing MMP-1 production due to UVB irradiation via inhibition of MMP gene expression. Importantly, the UVB-suppressed procollagen gene expression can be restored to normal by ß-thujaplicin. These findings indicate that ß-thujaplicin is a promising and potent agent to inhibit UVB-induced MMP-1 and MMP-3 gene expression in skin fibroblasts.


Assuntos
Chamaecyparis/química , Fibroblastos/enzimologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Monoterpenos/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Pele/enzimologia , Tropolona/análogos & derivados , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Tropolona/farmacologia , Raios Ultravioleta
11.
Dev Comp Immunol ; 33(5): 653-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19101590

RESUMO

The presence of phenoloxidase (PO) activity was detected in different developmental stages of the Pacific oyster, Crassostrea gigas. A significant reduction in PO activity was observed from the 6h embryo stage to the day 11 larvae by spectrophotometry. A progressive increase was also observed from the day 13 larvae right through to the juvenile stage. The microscopy studies with '6h embryo' and adult samples confirmed the presence of PO activity. Various modulators of PO activity were used to study the triggering of pro-phenoloxidase (proPO) activating system of C. gigas but also to confirm the exact nature of the monitored activity. The enzyme activation mechanisms appear to differ with the developmental stage: bacterial lipopolysaccharides constitute an early elicitor of the proPO-PO system, whereas a purified trypsin triggers proPO-PO system in C. gigas spat. Phenoloxidase activity was totally suppressed by PO-specific inhibitors such as beta-2-mercaptoethanol, sodium diethyldithiocarbonate and tropolone. This study demonstrated the selective response of PO-like activity by different elicitors and suggested that proPO-PO activating system, which is supposed to play an important function in non-self recognition and host immune reactions in oyster, is expressed early in the Pacific oyster, C. gigas.


Assuntos
Catecol Oxidase/metabolismo , Crassostrea/enzimologia , Crassostrea/crescimento & desenvolvimento , Precursores Enzimáticos/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Catecol Oxidase/imunologia , Crassostrea/imunologia , Crassostrea/ultraestrutura , Ditiocarb/farmacologia , Dopaminérgicos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/imunologia , Precursores Enzimáticos/imunologia , Hemócitos/efeitos dos fármacos , Hemócitos/enzimologia , Hemócitos/ultraestrutura , Imunidade Inata , Levodopa/farmacologia , Lipopolissacarídeos/farmacologia , Mercaptoetanol/farmacologia , Microscopia Eletrônica de Transmissão , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/imunologia , Tropolona/farmacologia , Tripsina/farmacologia
12.
Planta Med ; 74(8): 828-33, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18537078

RESUMO

In this study, we examined the modulatory effect of hinokitiol (HK) on the production of tumor necrosis factor (TNF)-alpha, a critical factor involved in skin inflammation and hair follicle apoptosis. HK effectively suppressed TNF-alpha production in lipopolysaccharide (LPS)-activated, macrophage-like (RAW264.7) cells. This compound also diminished mRNA synthesis of TNF-alpha, indicating that HK-mediated inhibition may occur at the transcriptional level. Moreover, this compound down-regulated the phosphorylation of PDK1, Akt/PKB, and ERK, resulting in a loss of nuclear factor (NF)-kappaB activation, which is detectable by immunoblotting and reporter gene assays. Therefore, these results suggest that HK may cure hair loss by suppressing factors that promote follicular apoptosis, such as TNF-alpha, in addition to stimulating new hair growth.


Assuntos
Anti-Infecciosos/farmacologia , Macrófagos/efeitos dos fármacos , Monoterpenos/farmacologia , NF-kappa B/antagonistas & inibidores , Tropolona/análogos & derivados , Fator de Necrose Tumoral alfa/metabolismo , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Macrófagos/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Transdução de Sinais , Tropolona/farmacologia
13.
Nat Prod Rep ; 25(1): 118-38, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18250899

RESUMO

Tropones and tropolones have been of increasing interest in the past few years; approximately 200 such materials occur in nature. This article reviews the distribution of these materials, the biosynthetic pathways for their production and their biological activities. There are 154 references.


Assuntos
Produtos Biológicos , Tropolona , Bactérias/química , Bactérias/metabolismo , Produtos Biológicos/biossíntese , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Fungos/química , Fungos/metabolismo , Estrutura Molecular , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Tropolona/análogos & derivados , Tropolona/química , Tropolona/metabolismo , Tropolona/farmacologia
14.
Bioresour Technol ; 99(11): 4871-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17977717

RESUMO

The ethanolic extract of Calocedrus macrolepis var. formosana heartwood was screened for antifungal compounds by agar dilution assay and liquid chromatography. Two compounds, beta-thujaplicin and gamma-thujaplicin, responsible for the antifungal property of C. macrolepis var. formosana heartwood were isolated by high performance liquid chromatography (HPLC), and identified by 1H NMR and 13C NMR. The antifungal activities of these two compounds were further evaluated against total 15 fungi, including wood decay fungi, tree pathogenic fungi and molds. The hexane soluble fraction showed the strongest antifungal activities among all fractions. beta-Thujaplicin and gamma-thujaplicin exhibited not only very strong antifungal activity, but also broad antifungal spectrum. The MIC values of beta-thujaplicin and gamma-thujaplicin were in the range of 5.0-50.0 microg/ml. In addition, scanning electron microscopy (SEM) was carried out to study the structural change of fungal hyphae induced by beta-thujaplicin. Strong cell wall shrinkage indicated the fungicidal effect could be attributed to the combined actions of metal chelating and cytoplasm leakage. It also suggests that the role of metal chelating is indispensable in the design of environmental-friendly fungicides.


Assuntos
Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Cupressaceae/química , Etanol/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Cupressaceae/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fungos/efeitos dos fármacos , Hexanos , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Solubilidade/efeitos dos fármacos , Árvores/efeitos dos fármacos , Árvores/microbiologia , Tropolona/análogos & derivados , Tropolona/farmacologia , Madeira/efeitos dos fármacos , Madeira/microbiologia
15.
Planta Med ; 71(10): 964-6, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16254832

RESUMO

Antiplasmodial and cytotoxicity testing of five highly oxygenated natural products (6R,12R,14R-colletoketol, 6R,11R,12R,14R-colletoketodiol, dihydrobotrydial, pycnidione, and 3R,4S-hydroxymellein), all derived from fungi of marine origin, showed one of them, pycnidione, to have activities against three different strains of Plasmodium falciparum in the sub-micromolar (microM) range. Although the mean selectivity index of 1 for the observed antiplasmodial activity of 4 is low, pycnidione's usefulness as a potential lead structure should not be ignored.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Fungos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fitoterapia , Plasmodium falciparum/efeitos dos fármacos , Tropolona/análogos & derivados , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Antimaláricos/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Células KB/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Testes de Sensibilidade Parasitária , Água do Mar , Relação Estrutura-Atividade , Tropolona/administração & dosagem , Tropolona/química , Tropolona/farmacologia , Tropolona/uso terapêutico
16.
J Vet Med Sci ; 67(12): 1243-7, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16397383

RESUMO

The antifungal activity of beta-thujaplicin was evaluated against 51 Malassezia pachydermatis strains isolated from canine ear canals with or without otitis externa. For comparison, sensitivity tests were performed on M. pachydermatis isolates for nystatin, ketoconazole, and terbinafine HCl, all clinically available antifungal agents. The minimal inhibition concentrations over 50% of the tested isolates (MIC50) were 3.13 microg/ml for beta-thujaplicin and nystatin, 0.016 microg/ml for ketoconazole, and 1.56 microg/ml for terbinafine HCl. The antifungal effect for M. pachydermatis of beta-thujaplicin compared favorably with commercial antifungal agents. None of the 51 M. pachydermatis isolates showed resistance against any of the tested antibiotics investigated in this study. Ten representative isolates of M. pachydermatis were subcultured for 30 generations at concentrations close to the MIC levels of beta-thujaplicin, nystatin, ketoconazole, and terbinafine HCl, and examined to determine whether they had acquired resistance to each drug. As a result, M. pachydermatis was found to achieve resistance more easily for ketoconazole and terbinafine HCl than for beta-thujaplicin or nystatin. The MIC50 of beta-thujaplicin did not change during the course of subculture, and it is thought that the potential development of a resistant strain is low, even with continuous infusion for otitis externa therapy. beta-Thujaplicin is an inexpensive and safe treatment with anti-inflammatory and deodorant effects that can be recommended as an effective remedy for canine otitis externa.


Assuntos
Antifúngicos/uso terapêutico , Dermatomicoses/veterinária , Doenças do Cão/tratamento farmacológico , Doenças do Cão/microbiologia , Farmacorresistência Fúngica , Malassezia/efeitos dos fármacos , Monoterpenos/uso terapêutico , Otite Externa/veterinária , Tropolona/análogos & derivados , Animais , Antifúngicos/farmacologia , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Cães , Cetoconazol/farmacologia , Cetoconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Nistatina/farmacologia , Nistatina/uso terapêutico , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Especificidade da Espécie , Terbinafina , Tropolona/farmacologia , Tropolona/uso terapêutico
17.
Eur J Med Chem ; 38(11-12): 949-57, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14642327

RESUMO

The preparation and evaluation as potential anti-protozoal agents of molecules bearing an endocyclic hydrazine moiety is presented. The synthetic route to this new series of compounds is straightforward, involving a hetero Diels-Alder reaction between different benzotropolone esters and diethyl azodicarboxylate (DEAD). While they show limited or no in vitro activity against Leishmania donovani, Plasmodium falciparum and Trypanosoma brucei rhodesiense, several of the compounds have activities against Trypanosoma cruzi in the 15.8-41.0 microM range. These activities are comparable to that of benznidazole (IC50 6.0 microM), the main chemotherapy employed in the treatment of T. cruzi infections. In addition, all but one of the new bicyclic hydrazine esters are virtually non-toxic, one of the most important drawbacks of currently available trypanocidal drugs.


Assuntos
Antiprotozoários/síntese química , Hidrazinas/síntese química , Tropolona/síntese química , Animais , Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hidrazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tropolona/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento
18.
Can J Microbiol ; 49(2): 78-84, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12718395

RESUMO

Listeria monocytogenes is an opportunistic intracellular pathogen capable of growth that requires iron for growth within phagocytic cells and virulence expression. In the presence of an appropriate concentration tropolone, an iron-chelating agent, growth of L. monocytogenes is completely inhibited. However, this inhibition can be relieved by addition of dopamine, norepinephrine, or ferric citrate. By selection on streptonigrin medium supplemented with tropolone and norepinephrine, we have obtained two spontaneous mutants, Lm-8 and Lm-15, with the same iron dependence but lower iron dependence than the wild-type Lm-B38. The association between iron requirement and virulence of the two mutants and the wild type was studied in the J774 macrophage cell line. One hour after phagocytosis by the J774 macrophage cell line, the two mutants and the parental strain displayed no difference in the number of phagocytosed bacteria. Twenty-four hours after phagocytosis, the number of bacteria within the surviving macrophages was identical for the wild strain and the two clones. However, only 40% of macrophage cells infected with Lm-8 and 90% of those infected with Lm-15 were alive after 24 h in comparison with macrophage cells infected with the parental strain Lm-B38. These data demonstrate that there is no direct correlation between iron requirement and virulence of L. monocytogenes in the J774 macrophage cell line.


Assuntos
Ferro/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidade , Macrófagos/microbiologia , Mutação , Catecolaminas/metabolismo , Células Cultivadas , Compostos Férricos/metabolismo , Listeria monocytogenes/efeitos dos fármacos , Macrófagos/metabolismo , Fagocitose , Tropolona/farmacologia , Virulência
19.
J Antimicrob Chemother ; 51(1): 113-22, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12493795

RESUMO

Beta-thujaplicin (hinokitiol) is a tropolone-related compound purified from the wood of Chamaecyparis obtusa, SIEB: et Zucc. and Thuja plicata D. Don. All Staphylococcus aureus isolates were inhibited by beta-thujaplicin with MICs of 1.56-3.13 mg/L. However, a paradoxical zone phenomenon occurred, with each isolate producing regrowth at higher beta-thujaplicin concentrations. Other antimicrobial agents showed a wide range of MICs. The combination of beta-thujaplicin and zinc oxide inhibited the paradoxical zone phenomenon, and enhanced killing activity against clinically isolated staphylococci. Large numbers of viable bacterial cells, especially S. aureus cells, were detected in the skin surface of atopic dermatitis, in comparison with those in healthy volunteers. The number of cells increased as the severity of the skin condition worsened. Topical application of beta-thujaplicin resulted in a reduction in the number of bacterial cells on the skin surface, and an improvement in skin condition after treatment. The results of this study suggest that the degree of reduction in the number of viable bacterial cells in an eczematous lesion of atopic dermatitis is related to the degree of improvement in skin condition.


Assuntos
Antibacterianos/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Monoterpenos/uso terapêutico , Staphylococcus aureus/efeitos dos fármacos , Tropolona/análogos & derivados , Tropolona/uso terapêutico , Adolescente , Adulto , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dermatite Atópica/patologia , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Monoterpenos/farmacologia , Staphylococcus aureus/citologia , Staphylococcus aureus/isolamento & purificação , Estatísticas não Paramétricas , Tropolona/farmacologia , Óxido de Zinco/farmacologia , Óxido de Zinco/uso terapêutico
20.
Appl Environ Microbiol ; 68(9): 4377-82, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12200290

RESUMO

Fenton reactions are believed to play important roles in wood degradation by brown rot fungi. In this context, the effect of tropolone (2-hydroxycyclohepta-2,4,6-trienone), a metal chelator, on wood degradation by Poria placenta was investigated. Tropolone (50 micro M) strongly inhibits fungal growth on malt agar, but this inhibition could be relieved by adding iron salts. With an experimental system containing two separate parts, one supplemented with tropolone (100 micro M) and the other not, it was shown that the fungus is able to reallocate essential minerals from the area where they are available and also to grow in these conditions on malt-agar in the presence of tropolone. Nevertheless, even in the presence of an external source of metals, P. placenta is not able to attack pine blocks impregnated with tropolone (5 mM). This wood degradation inhibition is related to the presence of the tropolone hydroxyl group, as shown by the use of analogs (cyclohepta-2,4,6-trienone and 2-methoxycyclohepta-2,4,6-trienone). Furthermore, tropolone possesses both weak antioxidative and weak radical-scavenging properties and a strong affinity for ferric ion and is able to inhibit ferric iron reduction by catecholates, lowering the redox potential of the iron couple. These data are consistent with the hypothesis that tropolone inhibits wood degradation by P. placenta by chelating iron present in wood, thus avoiding initiation of the Fenton reaction. This study demonstrates that iron chelators such as tropolone could be also involved in novel and more environmentally benign preservative systems.


Assuntos
Quelantes de Ferro/farmacologia , Polyporales/efeitos dos fármacos , Tropolona/farmacologia , Madeira , Antioxidantes/farmacologia , Interações Medicamentosas , Compostos Férricos/química , Ferro/química , Ferro/farmacologia , Oxirredução/efeitos dos fármacos , Polyporales/crescimento & desenvolvimento , Polyporales/metabolismo
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