Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.174
Filtrar
1.
Eur J Med Chem ; 186: 111883, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761385

RESUMO

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC50] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Xantina Desidrogenase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Desidrogenase/metabolismo
2.
Chemosphere ; 239: 124706, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493754

RESUMO

The remediation effect of organic acids in heavy metal contaminated soil was widely studied. However, the comprehensive evaluation of organic acids on micro-ecological environment in heavy metal contaminated soil was less known. Herein, this experiment was conducted to investigate the impact of malic acid, citric acid and oxalic acid on soil fertility, cadmium (Cd) speciation and ecotoxicity in contaminated soil. Especially, to evaluate the ecotoxicity of Cd, high-throughput sequencing was used to investigate the soil bacterial community structure and diversity after incubation with organic acids. The results showed that obvious changes in soil pH were not observed. Whereas, the contents of available phosphorus (Olsen-P) and alkali hydrolysable nitrogen (Alkeline-N) evidently increased with a significant difference. Furthermore, compared to control, the proportion of acetic acid-extractable Cd increased by 3.06-6.63%, 6.11-9.43% and 1.91-6.22% respectively in the groups amended with malic acid, citric acid and oxalic acid, which indicated that citric acid did better in improving the availability of Cd than malic acid and oxalic acid. In terms of biological properties, citric acid did best in bacteria count increase, enzyme activities and bacterial community structure improvement. Accordingly, these results provided a better understanding for the influence of organic acids on the micro-ecological environment in Cd contaminated soil, based on physicochemical and biological analysis.


Assuntos
Cádmio/toxicidade , Ácidos Carboxílicos/farmacologia , Recuperação e Remediação Ambiental/métodos , Microbiologia do Solo , Poluentes do Solo/química , Bactérias/efeitos dos fármacos , Cádmio/análise , Cádmio/química , Ácidos Carboxílicos/química , Ácido Cítrico/química , Ácido Cítrico/farmacologia , Ecotoxicologia , Poluição Ambiental/análise , Malatos/química , Malatos/farmacologia , Ácido Oxálico/química , Ácido Oxálico/farmacologia , Solo/química , Poluentes do Solo/análise
3.
Chem Commun (Camb) ; 56(8): 1179-1182, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31868184

RESUMO

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Carboxílicos/farmacologia , Fulerenos/farmacologia , Água/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Fulerenos/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Solubilidade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
4.
Chem Biodivers ; 16(11): e1900403, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515947

RESUMO

The antibacterial and antibiofilm activities of two new ruthenium complexes against E. coli, S. aureus, P. aeruginosa PAO1 (laboratory strain) and P. aeruginosa LES B58 (clinical strain) were evaluated. Complexes, mer-[RuIII (2-bimc)3 ] ⋅ H2 O (1) and cis-[RuIV Cl2 (2,3-pydcH)2 ] ⋅ 4H2 O (2), were obtained using aromatic carboxylic acid ligands, namely, 1H-benzimidazole-2-carboxylic acid (2-bimcH) and pyridine-2,3-dicarboxylic acid (2,3-pydcH2 ). Compounds were physicochemically characterized using X-ray diffraction, Hirshfeld surface analysis, IR and UV/VIS spectroscopies, as well as magnetic and electrochemical measurements. Structural characterization revealed that Ru(III) and Ru(IV) ions in the complexes adopt a distorted octahedral geometry. The intermolecular classical and weak hydrogen bonds, and π⋅⋅⋅π contacts significantly contribute to structure stabilization, leading to the formation of a supramolecular assembly. Biological studies have shown that the Ru complexes inhibit the growth of bacteria and biofilm formation by the tested strains and the complexes seem to be a potential as antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Ácidos Carboxílicos/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Ácidos Carboxílicos/química , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Rutênio/química , Staphylococcus aureus/efeitos dos fármacos
5.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509949

RESUMO

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.


Assuntos
Terapia por Captura de Nêutron de Boro , Boro/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Boro/química , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ésteres/química , Glicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Estrutura Molecular , Neoplasias/patologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Triazinas/química , Triazinas/farmacologia
6.
Molecules ; 24(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405197

RESUMO

Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 µM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 µM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 µM; SI: 114.8) compared with that of ACV (EC50: 2.8 µM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 µM; inhibition constant (Ki): 0.3 µM) compared with reference drugs aphidicolin (IC50: 0.8 µM; Ki: 0.4 µM) and ACV triphosphate (ACV-TP) (IC50: 0.9 µM; Ki: 0.5 µM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.


Assuntos
Antivirais , Benzoxepinas , Ácidos Carboxílicos , DNA Polimerase Dirigida por DNA , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/fisiologia , Líquens/química , Simulação de Acoplamento Molecular , Proteínas Virais , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Benzoxepinas/química , Benzoxepinas/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Chlorocebus aethiops , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Células Vero , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
7.
Eur J Med Chem ; 181: 111558, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369933

RESUMO

In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC50 values ranging from 0.0181 µM to 0.5677 µM. Specifically, compounds 10c and 10e, with IC50 values of 0.0240 µM and 0.0181 µM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
8.
Eur J Med Chem ; 181: 111559, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376568

RESUMO

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
9.
J Enzyme Inhib Med Chem ; 34(1): 1414-1425, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401901

RESUMO

The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of ß-lactam antibiotics. Infections caused by some bacteria which secrete metallo-ß-lactamases (enzymes that inactivate ß-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to ß-lactam antibiotics and MBL-inhibitor/ß-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-ß-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a-2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a-k shows the potent inhibitory effects against metallo-ß-lactamase (IMP-1) with the range of Kic values of 1.04-4.77 µM, they are not as potent as the candidate inhibitor.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Compostos de Sulfidrila/química , Tirosina/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ácidos Carboxílicos/química , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Serratia marcescens/efeitos dos fármacos , Serratia marcescens/enzimologia , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química
10.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 533-540, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357780

RESUMO

Objective: To analyze non-alcoholic steatohepatitis (NASH)-related differentially expressed genes (DEGs) by bioinformatics methods to find key pathways and potential therapeutic targets for NASH. Methods: GSE61260 chip was downloaded from the public microarray database and liver biopsy samples from 24 NASH cases and 38 healthy controls were included. The Limma software package in R language was used to screen DEGs under the condition of difference multiple > 1.5 and adj. P < 0.05. The clusterProfiler software package was used for GO analysis and KEGG analysis. The STRING online database was used for protein-protein interaction analysis, and the L1000 and DrugBank databases were used for drug prediction. Results: Compared with healthy control group, 857 DEGs were screened out in NASH group including 167 up-regulated genes and 690 down-regulated genes. GO analysis showed that DEGs were mainly involved in inflammation and cholesterol metabolism. KEGG analysis showed that DEGs were mainly enriched in PPAR, non-alcoholic fatty liver disease, oxidative phosphorylation and other signaling pathways. Among them, eight genes of ACSL4, CYP7A1, FABP4, FABP5, lipoprotein lipase, ME1, OLR1 and PLIN1 were enriched in PPAR signaling pathway, and 165 interaction nodes were formed with 47 DEGs-encoded proteins. Lipoprotein lipase interacted with 21 DEGs, and its up-regulated expression had improved lipid metabolism, insulin resistance and anti-inflammatory effects. Four drugs (gemfibrozil, bezafibrate, omega-3 carboxylic acid and glycyrrhizic acid) were screened by L1000 and DrugBank to activate lipoprotein lipase. Presently, these four drugs are clinically used to treat hypertriglyceridemia or to improve inflammation. In this regard, we speculated that the pharmacological effects of these four drugs had improved NASH by activating lipoprotein lipase to promote liver lipid metabolism and alleviate inflammation. Conclusion: PPAR signaling pathway is closely associated to the occurrence and development of NASH, and thereby lipoprotein lipase agonist is a new attempt to treat NASH.


Assuntos
Ativadores de Enzimas/farmacologia , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Bezafibrato/farmacologia , Biópsia , Ácidos Carboxílicos/farmacologia , Estudos de Casos e Controles , Biologia Computacional , Genfibrozila/farmacologia , Ácido Glicirrízico/farmacologia , Humanos , Hepatopatia Gordurosa não Alcoólica/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Depuradores Classe E
11.
Cardiovasc Diabetol ; 18(1): 86, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277657

RESUMO

BACKGROUND: Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure. METHOD: For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day). RESULT: Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3ß ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups. CONCLUSION: We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Cardiomiopatia Dilatada/complicações , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Resistência à Insulina , Miocárdio/metabolismo , Adulto , Idoso , Animais , Ácidos Carboxílicos/farmacologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Fibrose , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miocárdio/patologia , Oxirredução , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
12.
Eur J Med Chem ; 179: 123-132, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247374

RESUMO

The synthesis and in vitro anticancer activity of novel ß-carbolines is reported. New tryptamines have been prepared via hetero-Diels-Alder reaction of nitrosoalkenes with indoles and used to prepare functionalized ß-carbolines by the Pictet-Spengler approach. These included 6-substituted-ß-carboline-3-carboxylates and 3-(1H-tetrazol-5-yl)-ß-carbolines, whose synthesis is reported for the first time. Carboline-3-carboxylates derived from l-tryptophan methyl ester were also prepared. The structural diversity that was achieved allowed the discovery of impressive activities against a range cancer cell lines with the selectivity depending on the type of substitution pattern of the ß-carboline core. We have identified at least one ß-carboline derivative with GI50 ≤ 1  µM for each of the following human tumor cell lines: glioblastoma (U251), melanona (UACC-61), breast (MCF-7), ovarian expressing multiple-drug-resistance phenotype 4 (NCI-ADR/RES), renal (786-0), lung (NCI-H460), ovarian cancer (OVCAR-3), leukemia (K-562) and colon (HT29). These results demonstrated that the new ß-carboline derivatives are very promising anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Ácidos Carboxílicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbolinas/síntese química , Carbolinas/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248140

RESUMO

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Ácidos Carboxílicos/farmacologia , MicroRNAs/genética , Naftalenos/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Acetilação , Biomarcadores , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunofluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Naftalenos/química , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Proteólise , Interferência de RNA
14.
Appl Microbiol Biotechnol ; 103(13): 5367-5377, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053917

RESUMO

The bacterium, Bacillus amyloliquefaciens Pc3, was previously isolated from Antarctic seawater and has been found to show antagonistic activity against the fungus, Rhizoctonia solani ACCC 36316, which causes a severe disease known as Sclerotinia sclerotiorum in rapeseed plants. Bacillus lipopeptides had been widely used as biocontrol agents for plant diseases. In this study, we isolated 11 lipopeptide compounds from B. amyloliquefaciens Pc3 culture broth via reversed-phase high-performance liquid chromatography (RP-HPLC) and used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to identify these as iturin A (C14, C15, C16, C17), fengycin B (C14, C15, C16, C17), and surfactin (C14, C15, C16). We further found that the addition of exogenous alkanoic acids, including myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, octadecanoic acid, and nonadecanoic acid, to the bacterial growth media could promote lipopeptide production and enhance the antifungal activities of crude lipopeptide extracts from B. amyloliquefaciens Pc3. In addition, the transcriptional levels of three lipopeptide synthesis genes, ituD, fenA, and srfA-A, and two fatty acid metabolism-related genes, FabI, which encodes enoyl-ACP reductase, and FadB, which encodes enoyl-CoA hydratase, were found to be upregulated in cells grown with exogenous alkanoic acids. Among the six alkanoic acids tested, those with odd carbon chain lengths had a greater effect on lipopeptide production, antifungal activity, and target gene upregulation than those with even carbon chain lengths. These results provide a practical approach for the efficient production of lipopeptides in Bacillus amyloliquefaciens Pc3.


Assuntos
Antibiose , Antifúngicos/farmacologia , Bacillus amyloliquefaciens/efeitos dos fármacos , Bacillus amyloliquefaciens/metabolismo , Ácidos Carboxílicos/farmacologia , Lipopeptídeos/biossíntese , Bacillus amyloliquefaciens/genética , Ácidos Graxos/farmacologia , Lipopeptídeos/isolamento & purificação , Ácido Mirístico/farmacologia , Peptídeos Cíclicos/isolamento & purificação , Rhizoctonia/efeitos dos fármacos
15.
Am J Physiol Renal Physiol ; 317(1): F172-F186, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042061

RESUMO

The kidney uses specialized G protein-coupled receptors, including olfactory receptors (ORs), to act as sensors of molecules and metabolites. In the present study, we cloned and studied seven renal ORs, which we previously found to be expressed in the murine renal cortex. As most ORs are orphan receptors, our goal was to identify ligands for these ORs in the hope that this will guide future research into their functional roles. We identified novel ligands for two ORs: Olfr558 and Olfr90. For Olfr558, we confirmed activation by previously reported ligands and identified 16 additional carboxylic acids that activated this OR. The strongest activation of Olfr558 was produced by butyric, cyclobutanecarboxylic, isovaleric, 2-methylvaleric, 3-methylvaleric, 4-methylvaleric, and valeric acids. The primary in vivo source of both butyric and isovaleric acids is gut microbial metabolism. We also identified 14 novel ligands that activated Olfr90, the strongest of which were 2-methyl-4-propyl-1,3-oxathiane, 1-octen-3-ol, 2-octanol, and 3-octanol. Interestingly, 8 of these 14 ligands are of fungal origin. We also investigated the tissue distribution of these receptors and found that they are each found in a subset of "nonsensory" tissues. Finally, we examined the putative human orthologs of Olfr558 and Olfr90 and found that the human ortholog of Olfr558 (OR51E1) has a similar ligand profile, indicating that the role of this OR is likely evolutionarily conserved. In summary, we examined seven novel renal ORs and identified new ligands for Olfr558 and Olfr90, which imply that both of these receptors serve to detect metabolites produced by microorganisms.


Assuntos
Córtex Renal/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Odorantes/metabolismo , Animais , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacologia , Microbioma Gastrointestinal , Humanos , Córtex Renal/efeitos dos fármacos , Ligantes , Camundongos Endogâmicos C57BL , Transporte Proteico , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Receptores Odorantes/agonistas , Receptores Odorantes/genética , Transdução de Sinais , Distribuição Tecidual
16.
Nature ; 568(7750): 127-130, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30867591

RESUMO

The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner1-3. LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes2-6. Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs7-11. LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane8,9. Despite extensive cell-based characterization of the LAT1-4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown12-19. Here we report the cryo-electron microscopy structures of human LAT1-4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex. Together, our characterizations shed light on the architecture of the LAT1-4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease.


Assuntos
Microscopia Crioeletrônica , Cadeia Pesada da Proteína-1 Reguladora de Fusão/química , Cadeia Pesada da Proteína-1 Reguladora de Fusão/ultraestrutura , Transportador 1 de Aminoácidos Neutros Grandes/química , Transportador 1 de Aminoácidos Neutros Grandes/ultraestrutura , Aminoácidos/metabolismo , Sítios de Ligação , Transporte Biológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Dissulfetos/química , Dissulfetos/metabolismo , Cadeia Pesada da Proteína-1 Reguladora de Fusão/antagonistas & inibidores , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Modelos Moleculares , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Norbornanos/química , Norbornanos/farmacologia , Ligação Proteica , Conformação Proteica
17.
Bioorg Med Chem ; 27(7): 1382-1390, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819619

RESUMO

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.


Assuntos
Ácidos Carboxílicos/farmacologia , Cromanos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
18.
Chemosphere ; 225: 1-8, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30852260

RESUMO

Naphthols are industrial contaminants occurring widely in soils and waters. Remediation of organic pollutants can be done by chemical oxidation using persulfate. However, most research experiments testing degradation of organic pollutants have been done in ideal conditions, e.g. using a pure compound in pure water, and thus are weakly representative of real natural conditions where pollutants occur in complex mixtures of numerous organic compounds. Therefore we tested here the effect of the presence of small organic acids, as typical compounds occurring in natural media, on the degradation of 1-napthol with persulfate and iron oxides. Results show that organic acids decreased naphthol transformation by 3.7% for malic acid, 53.2% for tartaric acid, 72.3% for citric acid and 77% for oxalic acids, in a magnetite/persulfate system during 10 h. Meanwhile, the dissolved Fe species increased gradually with the reaction time; the highest concentration of Fe ions reached to ∼18 µM L-1 in aqueous phase. Electron paramagnetic resonance technique was applied to determine reactive oxygen species (ROS). The spin density of ·OH, detected as the main ROS, decreased initially, followed by gradually increase, suggesting that organic acids might inhibit the degradation of 1-naphthol by competing with ·OH. These findings disclose the high inhibition of the transformation by organic acids, and thus, more generally, imply that studies using only pure contaminants are weakly representative for remediation of real, natural samples.


Assuntos
Ácidos Carboxílicos/farmacologia , Recuperação e Remediação Ambiental/métodos , Compostos Férricos/química , Naftóis/química , Sulfatos/química , Poluentes Químicos da Água/química , Ácido Cítrico/química , Ferro/química , Peso Molecular , Espécies Reativas de Oxigênio , Tartaratos/química , Poluentes Químicos da Água/análise
19.
Chemosphere ; 222: 132-140, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30703652

RESUMO

The biodegradation potential of three bacterial cultures isolated from the rhizosphere of maize (Zea mays) and Sudan grass (Sorghum sudanense) grown in PAHs contaminated soils to degrade benzo[a]pyrene (BaP) and pyrene (PYR) was assessed. Of the three bacterial cultures isolated, two belonged to Gram-positive bacteria of phylum Actinobacteria namely Arthrobacter sp. MAL3 and Microbacterium sp. MAL2. The Gram-negative bacterial culture was Stenotrophomonas sp. MAL1, from the phylum Proteobacteria. The cultures were grown in the presence of BaP and PYR as sole carbon sources and with the addition of low molecular weight organic acids (LMWOAs) mixture. After 10-14 days of exposure, all the bacterial isolates exhibited a complete degradation of PYR with the addition of LMWOAs mixture, whereas only 38.7% of BaP was degraded by Stenotrophomonas sp. MAL1 with the addition of LMWOAs mixture. In addition, enhanced PAHs biodegradation by bacterial culture was observed when the PAHs present as mixture (BaP + PYR) with the addition of LMWOAs. Dioxygenase genes were detected in Stenotrophomonas sp. MAL1 (phnAC), and Arthrobacter sp. MAL3 (nidA and PAH-RHDα). Therefore, this study provides new insights on the influence of LMWOAs in enhancing the degradation of high molecular weight (HMW) PAHs in soil by rhizosphere bacterial cultures.


Assuntos
Bactérias/metabolismo , Biodegradação Ambiental , Ácidos Carboxílicos/química , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Poluentes do Solo/metabolismo , Bactérias/genética , Benzo(a)pireno , Ácidos Carboxílicos/farmacologia , Peso Molecular , Pirenos , Rizosfera , Zea mays/microbiologia
20.
Food Chem Toxicol ; 125: 479-493, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30735747

RESUMO

Seven selected microbial metabolites of proanthocyanidins (MMP), 3-phenylpropionic, 4-hydroxyphenyl acetic, 3-(4-hydroxyphenyl) propionic, p-coumaric, benzoic acid, pyrogallol (PG), and pyrocatechol (PC) were evaluated for their ability to reduce chemical carcinogen-induced toxicity in human lung epithelial cells (BEAS-2B) and human fetal hepatic cells (WRL-68). Cells pre-treated with MMP were exposed to a known chemical carcinogen, 4-[(acetoxymethyl) nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) to assess MMP-mediated cytoprotection and reduction of DNA damage. PG in BEAS-2B and PC in WRL-68 cells mitigated the NNKOAc-induced cytotoxicity. Pre-incubation of PG depicted significant protection against NNKOAc-induced DNA damage in BEAS-2B cells. PC in WRL-68 cells showed similar activity. To understand the mechanisms of PG- and PC-mediated DNA damage reduction, the effect on DNA damage response (DDR) proteins, cellular reactive oxygen species (ROS), total antioxidant capacity (TAC), glutathione peroxidase (GPx), and caspase activity were studied. PG and PC alter the DDR and may promote ATR-Chk1 and ATM-Chk2 pathways, respectively. Cellular oxidative stress induced by NNKOAc was mitigated by PG and PC through enhanced GPx expression and TAC. PG and PC suppressed the activation of the extrinsic apoptotic pathway (caspase 3 and 8) provoked by NNKOAc. MMP are beneficial in chemoprevention by reducing cellular DNA damage.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/toxicidade , Ácidos Carboxílicos/farmacologia , Ácidos Carboxílicos/toxicidade , Caspase 3/metabolismo , Caspase 8/metabolismo , Catecóis/farmacologia , Catecóis/toxicidade , Linhagem Celular , Humanos , Nitrosaminas/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Piridinas/efeitos adversos , Pirogalol/farmacologia , Pirogalol/toxicidade , Espécies Reativas de Oxigênio/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA