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1.
Nucleic Acids Res ; 49(16): 9374-9388, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34390346

RESUMO

The Y-family DNA polymerase η (Polη) is critical for the synthesis past damaged DNA nucleotides in yeast through translesion DNA synthesis (TLS). TLS is initiated by monoubiquitination of proliferating cell nuclear antigen (PCNA) and the subsequent recruitment of TLS polymerases. Although individual structures of the Polη catalytic core and PCNA have been solved, a high-resolution structure of the complex of Polη/PCNA or Polη/monoubiquitinated PCNA (Ub-PCNA) still remains elusive, partly due to the disordered Polη C-terminal region and the flexibility of ubiquitin on PCNA. To circumvent these obstacles and obtain structural insights into this important TLS polymerase complex, we developed photo-activatable PCNA and Ub-PCNA probes containing a p-benzoyl-L-phenylalanine (pBpa) crosslinker at selected positions on PCNA. By photo-crosslinking the probes with full-length Polη, specific crosslinking sites were identified following tryptic digestion and tandem mass spectrometry analysis. We discovered direct interactions of the Polη catalytic core and its C-terminal region with both sides of the PCNA ring. Model building using the crosslinking site information as a restraint revealed multiple conformations of Polη in the polymerase complex. Availability of the photo-activatable PCNA and Ub-PCNA probes will also facilitate investigations into other PCNA-containing complexes important for DNA replication, repair and damage tolerance.


Assuntos
DNA Polimerase Dirigida por DNA/genética , DNA/biossíntese , Antígeno Nuclear de Célula em Proliferação/genética , Proteínas de Saccharomyces cerevisiae/genética , Ubiquitina/genética , Benzofenonas/farmacologia , DNA/genética , Replicação do DNA/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/ultraestrutura , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/ultraestrutura , Substâncias Macromoleculares/química , Substâncias Macromoleculares/ultraestrutura , Mutação/genética , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Antígeno Nuclear de Célula em Proliferação/química , Antígeno Nuclear de Célula em Proliferação/ultraestrutura , Ligação Proteica/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/ultraestrutura , Ubiquitina/química , Ubiquitina/ultraestrutura
2.
Chem Pharm Bull (Tokyo) ; 69(11): 1039-1044, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34456215

RESUMO

Exposure to UV radiation damages the skin and increases the risk of skin cancer. Sunscreen is used to protect the skin from the harmful effects of UV radiation. However, the chemical UV filters used in sunscreen can show toxicity and cause allergic reactions. A safe sunscreen that includes a lower content of chemical UV filters and exerts an excellent effect on UV protection needs to be developed. The objective of this study was to investigate whether the addition of afzelin to sunscreen could improve the sun protection factor (SPF). A synergistic effect between afzelin and organic sunscreen agents including padimate O and oxybenzone was confirmed. Interestingly, 100% in vitro SPF-boosting was observed when afzelin (0.05%) was applied with a standard SPF formulation containing organic sunscreens while afzelin alone had no contribution to the SPF. In vivo SPF analysis of the standard SPF formulation showed an SPF value of 13.3 that increased to 20.1 when supplemented with afzelin (0.05%). Additionally, afzelin showed no skin irritation in a human trial. These results suggest that afzelin is useful as a natural additive in sunscreen formulations and provides an SPF-boosting effect. Afzelin supplementation to the formulation showed the potential to reduce the use of synthetic photoprotectors, which could minimize the risk of synthetic agent toxicity.


Assuntos
Cosméticos/química , Manosídeos/química , Proantocianidinas/química , Fator de Proteção Solar/métodos , Protetores Solares/química , Adolescente , Adulto , Benzofenonas/farmacologia , Ensaios Clínicos como Assunto , Cosméticos/farmacologia , Composição de Medicamentos , Feminino , Humanos , Masculino , Manosídeos/farmacologia , Pessoa de Meia-Idade , Proantocianidinas/farmacologia , Pele , Protetores Solares/farmacologia , Raios Ultravioleta , para-Aminobenzoatos/farmacologia
3.
Food Funct ; 12(14): 6432-6441, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34075995

RESUMO

Ten new polyisoprenylated benzophenone derivatives, 4,8-epi-uralione F (1), 4,8-epi-uralione G (2), uralione S (3), coccinone J (4), 6-epi-coccinone C (5), coccinone I (6), 36-hydroxy-guttiferone J (7), multiflorone I (8), garciniagifolone F (9) and 36-hydroxy-garciniagifolone F (10), were isolated from the fruits of Garcinia cambogia, along with seven known analogues. The structures of the new compounds were established based on the detailed analysis of 1D and 2D nuclear magnetic resonance (NMR) spectra and high resolution electrospray ionization mass spectrometra (HRESIMS), and their absolute configurations were determined from the electronic circular dichroism (ECD) spectra. All the isolates were tested for their inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The results indicated that compound 1 displayed a potent NO inhibitory effect with an IC50 value of 41.60 ± 0.17 µM. Furthermore, compound 1 suppressed inducible NO synthase (iNOS) expression in a dose-dependent manner through inhibiting the activation of nuclear factor-κB (NF-κB).


Assuntos
Anti-Inflamatórios/farmacologia , Benzofenonas/farmacologia , Frutas/química , Garcinia cambogia/química , Animais , Anti-Inflamatórios/química , Benzofenonas/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular/métodos , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7 , Espectrometria de Massas por Ionização por Electrospray/métodos
4.
Chem Biodivers ; 18(8): e2100307, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34086414

RESUMO

Brazilian green and red propolis stand out as commercial products for different medical applications. In this article, we report the antimicrobial activities of the hydroalcoholic extracts of green (EGP) and red (ERP) propolis, as well as guttiferone E plus xanthochymol (8) and oblongifolin B (9) from red propolis, against multidrug-resistant bacteria (MDRB). We undertook the minimal inhibitory (MIC) and bactericidal (MBC) concentrations, inhibition of biofilm formation (MICB50 ), catalase, coagulase, DNase, lipase, and hemolysin assays, along with molecular docking simulations. ERP was more effective by displaying MIC and MBC values <100 µg mL-1 . Compounds 8 and 9 displayed the lowest MIC values (0.98 to 31.25 µg mL-1 ) against all tested Gram-positive MDRB. They also inhibited the biofilm formation of S. aureus (ATCC 43300 and clinical isolate) and S. epidermidis (ATCC 14990 and clinical isolate), with MICB50 values between 1.56 and 6.25 µg mL-1 . The molecular docking results indicated that 8 and 9 might interact with the catalase's amino acids. Compounds 8 and 9 have great antimicrobial potential.


Assuntos
Anti-Infecciosos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Própole/química , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Benzofenonas/química , Benzofenonas/isolamento & purificação , Benzofenonas/metabolismo , Benzofenonas/farmacologia , Sítios de Ligação , Biofilmes/efeitos dos fármacos , Brasil , Catalase/química , Catalase/metabolismo , Domínio Catalítico , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Própole/metabolismo , Própole/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
5.
Int J Biol Macromol ; 181: 956-965, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33878358

RESUMO

Chitosan (Cs) was cross-linked with four various quantities of 4,4'-(5,5'­carbonylbis(1,3-dioxoisoindoline-5,2-diyl))dibenzoyl isothiocyanate. Elemental analysis, FTIR and 1H NMR spectroscopy assured that the amino groups of chitosan reacted with the isothiocyanate groups of the cross-linker producing four new hydrogels namely as BBTU-Cs-1, BBTU-Cs-2, BBTU-Cs-3, and BBTU-Cs-4 according to the increment of their cross-linking content, respectively. SEM showed their porous structures and XRD indicated their amorphous nature. Their swell ability increased with decreasing the medium pH value and with increasing cross-linking density. In comparison with the popular COX inhibitor Celecoxib, these hydrogels showed an inhibition activity towards COX enzymes with selective inhibition towards COX-2. Their inhibition activity could be arranged as follows: Celecoxib > BBTU-Cs-4 > BBTU-Cs-3 > BBTU-Cs-2 > BBTU-Cs-1. BBTU-CS-4 hydrogel exhibited a potent inhibition against COX-2 (IC50 0.42 µg/ml) compared with that observed for the standard Celecoxib (IC50 0.26 µg/ml). BBTU-Cs-4 is more potent against H. pylori compared to the other hydrogels. BBTU-Cs-4 at a concentration of 7.81 µg/ml is able to kill 100% of the H. pylori and exhibits a preferential ability to inhibit 89.35% of COX-2 than COX-1 (0%). These findings make BBTU-Cs-4 a promising anti-H. pylori and selective anti-inflammatory agent.


Assuntos
Quitosana/farmacologia , Helicobacter pylori/efeitos dos fármacos , Hidrogéis/farmacologia , Inflamação/tratamento farmacológico , Antibacterianos/química , Antibacterianos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Quitosana/química , Reagentes para Ligações Cruzadas , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Helicobacter pylori/patogenicidade , Humanos , Hidrogéis/química , Inflamação/microbiologia , Inflamação/patologia , Tioureia/química , Tioureia/farmacologia
6.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916806

RESUMO

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.


Assuntos
Isoquinolinas/análise , Isoquinolinas/síntese química , Nitrilas/química , Pirróis/química , Benzofenonas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Prótons
7.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836600

RESUMO

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias/genética , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Survivina/genética , Telomerase/genética , Benzofenonas/farmacologia , Benzofenonas/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Survivina/metabolismo , Telomerase/metabolismo
8.
Chem Res Toxicol ; 34(4): 1140-1149, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33684284

RESUMO

Benzophenone-1 (BP-1), one of the commonly used ultraviolet filters, has caused increasing public concern due to frequently detected residues in environmental and recreational waters. Its susceptibility to residual chlorine and the potential to subsequently trigger endocrine disruption remain unknown. We herein investigated the chlorination of BP-1 in swimming pool water and evaluated the endocrine disruption toward the human androgen receptor (AR). The structures of monochlorinated (P1) and dichlorinated (P2) products were separated and characterized by mass spectrometry and 1H-1H NMR correlation spectroscopy. P1 and P2 exhibited significantly higher antiandrogenic activity in yeast two-hybrid assays (EC50, 6.13 µM and 9.30 µM) than did BP-1 (12.89 µM). Our 350 ns Gaussian accelerated molecular dynamics simulations showed the protein dynamics in a long-time scale equilibrium, and further energy calculations revealed that although increased hydrophobic interactions are primarily responsible for enhanced binding affinities between chlorinated products and the AR ligand binding domain, the second chloride in P2 still hinders the complex motion because of the solvation penalty. The mixture of BP-1-P1-P2 elicited additive antiandrogenic activity, well fitted by the concentration addition model. P1 and P2 at 1 µM consequently downregulated the mRNA expression of AR-regulated genes, NKX3.1 and KLK3, by 1.7-9.1-fold in androgen-activated LNCaP cells. Because chlorination of BP-1 occurs naturally by residual chlorine in aquatic environments, our results regarding enhanced antiandrogenic activity and disturbed AR signaling provided evidence linking the use of personal care products with potential health risks.


Assuntos
Benzofenonas/farmacologia , Disruptores Endócrinos/farmacologia , Simulação de Dinâmica Molecular , Receptores Androgênicos/metabolismo , Benzofenonas/síntese química , Benzofenonas/química , Sobrevivência Celular/efeitos dos fármacos , Disruptores Endócrinos/síntese química , Disruptores Endócrinos/química , Halogenação , Humanos , Estrutura Molecular , Células Tumorais Cultivadas
9.
Bioorg Med Chem ; 33: 116035, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33550084

RESUMO

Microglia are the principle cell type driving sustained neuroinflammation in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis. Interestingly, microglia locked into a chronic M1 pro-inflammatory phenotype significantly up-regulate the cannabinoid receptor 2 (CB2) expression. Our approach to exploiting CB2 as a therapeutic target in neuroinflammatory diseases focuses on the development of selective CB2 inverse agonists to shift microglia bias to a M2 pro-wound healing phenotype. Herein we report work designed to refine the structure activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone CB2 inverse agonist scaffold. A series of analogs of our lead compound SMM-189 were synthesized and measured for affinity/selectivity, potency, and efficacy in regulating cAMP production and ß-arrestin recruitment. In this series compound 40 demonstrated a significant increase in potency and efficacy for cAMP stimulation compared to SMM-189. Akin to our lead SMM-189, this compound was highly efficacious in biasing microglia to an M2 pro-wound healing phenotype in LPS stimulated cell lines. These results advance our understanding of the structure-activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold and provide further support for regulating microglia activation using CB2 inverse agonists.


Assuntos
Benzofenonas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Benzofenonas/síntese química , Benzofenonas/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Sci Rep ; 11(1): 3602, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574464

RESUMO

To prevent infections associated with medical implants, various antimicrobial silver-coated implant materials have been developed. However, these materials do not always provide consistent antibacterial effects in vivo despite having dramatic antibacterial effects in vitro, probably because the antibacterial effects involve silver-ion-mediated reactive oxygen species generation. Additionally, the silver application process often requires extremely high temperatures, which damage non-metal implant materials. We recently developed a bacteria-resistant coating consisting of hydroxyapatite film on which ionic silver is immobilized via inositol hexaphosphate chelation, using a series of immersion and drying steps performed at low heat. Here we applied this coating to a polymer, polyetheretherketone (PEEK), and analyzed the properties and antibacterial activity of the coated polymer in vitro and in vivo. The ionic silver coating demonstrated significant bactericidal activity and prevented bacterial biofilm formation in vitro. Bio-imaging of a soft tissue infection mouse model in which a silver-coated PEEK plate was implanted revealed a dramatic absence of bacterial signals 10 days after inoculation. These animals also showed a strong reduction in histological features of infection, compared to the control animals. This innovative coating can be applied to complex structures for clinical use, and could prevent infections associated with a variety of plastic implants.


Assuntos
Biofilmes/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Próteses e Implantes/microbiologia , Infecções Estafilocócicas/prevenção & controle , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Durapatita/química , Durapatita/farmacologia , Humanos , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Polímeros/química , Polímeros/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Prata/química , Prata/farmacologia , Infecções Estafilocócicas/microbiologia
12.
J Environ Sci Health B ; 56(1): 54-63, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33156729

RESUMO

Twenty-two strains of Trichoderma spp. (T. harzianum species complex [THSC], Trichoderma aggressivum f. europaeum, Trichoderma pleuroti, and Trichoderma pleuroticola) causing green mold disease on edible mushrooms (button mushroom, shiitake and oyster mushroom), collected during 2004-2018 from four countries (Serbia, North Macedonia, Croatia, and Hungary) were examined. Based on their ITS (internal transcribed spacer) sequences, strains from shiitake mushroom in Serbia were identified as members of the THSC, while in samples obtained from Serbian and North-Macedonian oyster mushroom farms THSC, T. pleuroti and T. pleuroticola were detected, which represent the first findings in the region. In fungicide susceptibility tests, all examined Trichoderma strains were found to be highly sensitive to prochloraz (ED50<0.4 µg mL-1) and considerably susceptible to metrafenone (ED50 < 4 µg mL-1). The most sensitive taxon to both fungicides was THSC from oyster mushroom. The toxicity of metrafenone was satisfying and strains from oyster mushroom showed the highest sensitivity (ED50 < 1.43 µg mL-1), while strains originating from button mushroom and shiitake displayed similar susceptibilities (ED50 < 3.64 µg mL-1). After additional in vivo trials, metrafenone might also be recommended for the control of green mold disease in mushroom farms.


Assuntos
Benzofenonas/farmacologia , Fungicidas Industriais/farmacologia , Imidazóis/farmacologia , Trichoderma/efeitos dos fármacos , Agaricus/efeitos dos fármacos , Agaricus/crescimento & desenvolvimento , Europa Oriental , Testes de Sensibilidade Microbiana , Trichoderma/classificação
13.
Transfusion ; 61(2): 594-602, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33219568

RESUMO

BACKGROUND: The current approach to reducing bacterial contamination in blood transfusion products is through detection or pathogen reduction methods, some of which utilize ultraviolet (UV) light photosensitizers. A small number of photosensitizers are being used as single agents in combination with UV light, but their efficacy can be limited against some pathogens. Benzophenone (BP) and vitamins B1, B6, and K3 have been identified as effective UVA photosensitizers for inactivation of bacteria. We evaluated whether combining pairs of photosensitizers in this group would have synergistic bactericidal effects on Gram-negative and Gram-positive bacteria. STUDY DESIGN AND METHODS: Bacteria species of Escherichia coli, Bacillus cereus, Staphylococcus aureus, and Klebsiella pneumoniae were mixed with 0 to 100 mM concentrations of photosensitizers and exposed to UVA irradiation at 18 J/cm2 to assess their bactericidal effects. RESULTS: Single photosensitizers irradiated with UVA produced a range of bactericidal activity. When combined in pairs, all demonstrated some synergistic bactericidal effects with up to 4-log reduction above the sum of activities of individual molecules in the pair against bacteria in plasma. Photosensitizer pairs with BP had the highest synergism across all bacteria. With vitamin K3 in the pair, synergism was evident for Gram-positive but not for Gram-negative bacteria. Vitamin B1 and vitamin B6 had the least synergism. These results indicate that a combination approach with multiple photosensitizers may extend effectiveness of pathogen reduction in plasma. CONCLUSIONS: Combining photosensitizers in pathogen reduction methods could improve bactericidal efficacy and lead to use of lower concentrations of photosensitizers to reduce toxicities and unwanted side effects.


Assuntos
Antibacterianos/efeitos da radiação , Benzofenonas/efeitos da radiação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fármacos Fotossensibilizantes/efeitos da radiação , Tiamina/efeitos da radiação , Raios Ultravioleta , Vitamina B 6/efeitos da radiação , Vitamina K 3/efeitos da radiação , Absorção de Radiação , Antibacterianos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Sinergismo Farmacológico , Bactérias Gram-Negativas/efeitos da radiação , Bactérias Gram-Positivas/efeitos da radiação , Humanos , Estrutura Molecular , Fotoquímica , Fármacos Fotossensibilizantes/farmacologia , Tiamina/química , Tiamina/farmacologia , Vitamina B 6/química , Vitamina B 6/farmacologia , Vitamina K 3/química , Vitamina K 3/farmacologia
14.
Nat Prod Res ; 35(15): 2489-2497, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31674853

RESUMO

Butyrolactone I, one of the major secondary metabolites of fungus Aspergillus terreus, is a selective cdc2 kinase inhibitor. In the present study, the metabolism of butyrolactone I in male Wistar rats was investigated by characterising metabolites excreted into faeces. Following an oral dose of 40 mg/kg butyrolactone I, two phase I metabolites were isolated from the faeces of rat. The new structure was identified on the spectroscopic data analysis. The new compound V1 and known compound V2 were tested for their cytotoxicity, antimicrobial and antioxidant activity. V1 and V2 showed significant free radical scavenging ability. V2 also showed strong inhibitory activity against Staphylococcus aureus.


Assuntos
4-Butirolactona , Aspergillus/química , Benzofenonas , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Antibacterianos/farmacologia , Benzofenonas/farmacologia , Fezes , Sequestradores de Radicais Livres/farmacologia , Masculino , Ratos , Ratos Wistar , Staphylococcus aureus/efeitos dos fármacos
15.
Molecules ; 25(23)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33276654

RESUMO

Garcinia morella (Gaertn.) Desr. is an evergreen tree that yields edible fruits, oil, and resin. It is a source of "gamboge", a gum/resin that has a wide range of uses. The fruits, leaves, and seeds of this tree are rich in bioactive compounds, including xanthones, flavonoids, phenolic acids, organic acids, and terpenoids. Evidence from different studies has demonstrated the antioxidant, antifungal, antiviral, hepatoprotective, anticancer, anti-inflammatory, antibacterial, and larvicidal activities of the fruit, leaf, and seed extracts of G. morella. This review summarizes the information on the phytochemicals of G. morella and the biological activities of its active constituents.


Assuntos
Garcinia/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Anti-Infecciosos , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Benzofenonas/química , Benzofenonas/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Compostos Fitoquímicos/isolamento & purificação , Casca de Planta/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Relação Estrutura-Atividade , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/farmacologia , Xantonas/química , Xantonas/farmacologia
16.
Bioorg Chem ; 104: 104339, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142411

RESUMO

Ten previously undescribed compounds, including five prenylated xanthones (1-5), two caged xanthones (16-17) and three rearranged benzophenones (27-29), together with nineteen known compounds were isolated from the fruits of Garcinia bracteata. Their structures were established on the basis of spectroscopic analysis, electronic circular dichroism calculations, and X-ray crystallographic data. Compound 17 was a caged xanthone bearing a rare 8, 8a-epoxy moiety. Compound 28 belonged to the rearranged benzophenones with rare 2, 7-dioxabicyclo-[2.2.1] heptane moiety fused at C-2 and C-3 respectively. The antiproliferative and anti-inflammatory activities of all isolated compounds were evaluated. Compounds 23 and 24 exhibited remarkable inhibitory activities against three human cancer cell lines (HepG2, T98, MCF-7) with IC50 values ranging from 3.21 ± 1.00 to 6.27 ± 1.03 µM. Moreover, compounds 20 and 24 also displayed significant inhibitory effects against NO production with IC50 values of 1.22 ± 0.01 and 1.77 ± 0.23 µM respectively. These results enrich the structural diversities of xanthones and benzophenones from Garcinia plants. Neobractatin (24) due to its anti-tumor and anti-inflammatory effects is worth further investigation in anticancer research.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/farmacologia , Frutas/química , Garcinia/química , Óxido Nítrico/antagonistas & inibidores , Xantonas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofenonas/química , Benzofenonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade , Xantonas/química , Xantonas/isolamento & purificação
17.
Pak J Pharm Sci ; 33(3): 1147-1153, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-33191241

RESUMO

Fifteen benzophenone thiosemicarbazones were synthesized and their in vitro antiglycation activity was evaluated. The most active compound 2 (IC50 = 118.15±2.41µM) showed two folds potent activity than the standard, rutin (IC50 = 294.5±1.5µM). Compounds 1 and 3-7 showed good to moderate antiglycation activity in the range of 204.14 - 488.54µM. These compounds were also evaluated for antioxidant activity. Their structure-activity relationships have been developed. The results reveal the potential of these compounds as leads for further studies towards the development of antidiabetic drugs.


Assuntos
Antioxidantes/farmacologia , Benzofenonas/farmacologia , Hipoglicemiantes/farmacologia , Tiossemicarbazonas/farmacologia , Antioxidantes/síntese química , Benzofenonas/síntese química , Compostos de Bifenilo/química , Produtos Finais de Glicação Avançada/química , Hipoglicemiantes/síntese química , Estrutura Molecular , Picratos/química , Soroalbumina Bovina/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química
18.
Molecules ; 25(21)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158263

RESUMO

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose-response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.


Assuntos
Benzofenonas , Corantes Fluorescentes , Imagem Óptica , Plasmodium falciparum/metabolismo , Proteoma/metabolismo , Proteínas de Protozoários/metabolismo , Benzofenonas/química , Benzofenonas/farmacologia , Eritrócitos/parasitologia , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Plasmodium falciparum/citologia
19.
BMC Cancer ; 20(1): 1057, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33143663

RESUMO

BACKGROUND: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study. METHODS: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining. RESULTS: Short-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046). CONCLUSIONS: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.


Assuntos
Benzofenonas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/terapia , Valina/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Benzofenonas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Fracionamento da Dose de Radiação , Esquema de Medicação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Radioterapia , Resultado do Tratamento , Valina/administração & dosagem , Valina/farmacologia
20.
Photochem Photobiol Sci ; 19(10): 1460-1469, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33026028

RESUMO

The overexposure of the skin to ultraviolet (UV) radiation may lead to oxidative stress, resulting in severe damage. The prevention of skin injuries through the topical application of natural compounds rich in antioxidants, such as propolis extracts, has shown promising results. In Brazil, the "red propolis" extract has stood out due to its complex constitution, based mainly on polyprenylated benzophenones (BZP). However, although the use of red propolis extracts has been shown to be encouraging, their addition in topical formulations is limited by the low solubility of BZP. For this reason, this study aimed to develop topical nanoemulgels containing Brazilian red propolis (BRP) extract to increase the potential of topical application, and the evaluation of skin protection against UVA/UVB radiation damage by means of protein carbonylation, protein thiol content and TBARS assays. The nanoemulgels were obtained by adding gelling polymer to nanoemulsions that were previously prepared by spontaneous emulsification. In this sense, a nanoemulgel containing BRP extract-loaded nanoemulsions (H-NE) and a nanoemulgel containing BRP extract-loaded nanoemulsions with DOTAP (H-NE/DT) were prepared. The physicochemical characterization of nanoemulgels showed monodisperse populations of 200-300 nm. The H-NE zeta potential was -38 mV, while that of H-NE/DT was +36 mV. BZP content in the formulations was around 0.86 mg g-1. These parameters remained stable for 90 days under cold storage. H/NE and H-NE/DT presented a non-Newtonian pseudoplastic rheological behavior. Permeation/retention studies, through porcine ear skin, showed the highest BZP retention (18.11 µg cm-2 after 8 h) for H-NE/DT, which also demonstrated, in an in vitro study, the highest ability to protect skin against oxidative damage after UVA/UVB radiation exposure. The results concerning the antioxidant activity revealed that formulations containing the BRP n-hexane extract were the most promising in combating oxidative stress, probable due to the presence of polyprenylated BZP. Altogether, the outcomes of this study suggest that nanoemulgels have suitable characteristics for topical application, and may be an alternative for the prevention of oxidative skin damage caused by UVA/UVB radiation.


Assuntos
Antioxidantes/farmacologia , Benzofenonas/farmacologia , Nanopartículas/química , Própole/farmacologia , Substâncias Protetoras/farmacologia , Pele/efeitos dos fármacos , Animais , Antioxidantes/química , Benzofenonas/química , Brasil , Orelha , Géis/química , Géis/farmacologia , Conformação Molecular , Tamanho da Partícula , Própole/química , Substâncias Protetoras/química , Propriedades de Superfície , Suínos , Raios Ultravioleta
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