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1.
J Asian Nat Prod Res ; 20(5): 488-493, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29191050

RESUMO

A new isoprenylated sanggenon-type flavanone, nigrasin K (1), together with three known analogs (2-4) and five known Diels-Alder adducts (5-9), were isolated from the twigs of Morus nigra. Their structures were elucidated by spectroscopic methods. Sanggenon M (2), chalcomoracin (5), sorocein H (6), kuwanon J (7), sanggenon C (8), and sanggenon O (9) showed significant inhibitory effects on mushroom tyrosinase.


Assuntos
Monofenol Mono-Oxigenase/antagonistas & inibidores , Morus/química , Fenóis/química , Fenóis/farmacologia , Estrutura Molecular
2.
PLoS One ; 12(4): e0175465, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28406943

RESUMO

There has been growing recognition of the essential roles of citrate in biomechanical properties of mineralized tissues, including teeth and bone. However, the sources of citrate in these tissues have not been well defined, and the contribution of citrate to the regulation of odontogenesis and osteogenesis has not been examined. Here, tooth and bone phenotypes were examined in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient C57BL/6 mice at 13 and 32 weeks of age. Slc13a5 deficiency led to defective tooth development, characterized by absence of mature enamel, formation of aberrant enamel matrix, and dysplasia and hyperplasia of the enamel organ epithelium that progressed with age. These abnormalities were associated with fragile teeth with a possible predisposition to tooth abscesses. The lack of mature enamel was consistent with amelogenesis imperfecta. Furthermore, Slc13a5 deficiency led to decreased bone mineral density and impaired bone formation in 13-week-old mice but not in older mice. The findings revealed the potentially important role of citrate and Slc13a5 in the development and function of teeth and bone.


Assuntos
Densidade Óssea/fisiologia , Ácido Cítrico/metabolismo , Esmalte Dentário/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Osteogênese/fisiologia , Simportadores/metabolismo , Animais , Transportadores de Ácidos Dicarboxílicos/deficiência , Camundongos , Camundongos Knockout , Simportadores/deficiência
3.
Phytother Res ; 29(7): 1040-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25826437

RESUMO

(2'R)-2',3'-Dihydro-2'-(1-hydroxy-1-methylethyl)-2,6'-bibenzofuran-6,4'-diol (DHMB) is a natural compound extracted from Morus notabilis. It was found that DHMB acts as a competitive inhibitor against mushroom tyrosinase with a Ki value of 14.77 µM. Docking results further indicated that it could form strong interactions with one copper ion with a distance of 2.7 Å, suggesting the mechanism of inhibition might be due to chelating copper ions in the active site. Furthermore, melanin production in B16-F10 murine melanoma cells was significantly inhibited by DHMB in a concentration-dependent manner without cytotoxicity. The results of western blotting also showed that DHMB decreased 3-isobuty-1-methxlzanthine-induced mature tyrosinase expression. Taken together, these findings indicated that DHMB may be a new promising pigmentation-altering agent for agriculture, cosmetic, and therapeutic applications.


Assuntos
Agaricales/enzimologia , Benzofuranos/química , Melaninas/biossíntese , Melanoma Experimental/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Inibidores Enzimáticos/química , Camundongos , Simulação de Acoplamento Molecular , Morus/química
4.
Eur J Med Chem ; 90: 241-50, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25461324

RESUMO

Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4.


Assuntos
Derivados de Benzeno/farmacologia , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Lipólise/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
5.
Acta Pharmacol Sin ; 34(11): 1397-402, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24077632

RESUMO

AIM: Fatty acid-binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. The aim of this study was to find new inhibitors of FABP4 for the treatment of type 2 diabetes. METHODS: Human FABP4 protein was expressed, and its inhibitors were detected in 1,8-ANS displacement assay. The effect of the inhibitor on lipolysis activity was examined in mouse 3T3-L1 preadipocytes. The db/db mice were used to evaluate the anti-diabetic activity of the inhibitor. Molecular docking and site-directed mutagenesis studies were carried out to explore the binding mode between the inhibitor and FABP4. RESULTS: From 232 compounds tested, benzbromarone (BBR), an old uricosuric drug, was discovered to be the best inhibitor of FABP4 with an IC50 value of 14.8 µmol/L. Furthermore, BBR (25 µmol/L) significantly inhibited forskolin-stimulated lipolysis in 3T3-L1 cells. Oral administration of BBR (25 or 50 mg/kg, for 4 weeks) dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db/db mice. Molecular docking revealed that the residues Ser55, Asp76, and Arg126 of FABP4 formed important interactions with BBR, which was confirmed by site-directed mutagenesis studies. CONCLUSION: BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.


Assuntos
Benzobromarona/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Células 3T3-L1 , Animais , Benzobromarona/administração & dosagem , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Uricosúricos/administração & dosagem , Uricosúricos/farmacologia
6.
Planta Med ; 79(11): 933-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23804039

RESUMO

Nowadays, abnormal hyperpigmentation in human skin such as melasma, freckles, and chloasma has become a serious esthetic problem. Cutaneous depigmenting agents could be used to treat these hyperpigmentation-associated dieseases. Dodoviscin A is a natural product isolated from the aerial parts of Dodonaea viscosa. In the present study, we evaluated the effect of dodoviscin A on melanin production in B16-F10 melanoma cells for the first time. We found that dodoviscin A inhibited melanin biosynthesis induced by 3-isobutyl-1-methylxanthine and PD98059 significantly, and there was no obvious effect on the viability of dodoviscin A-treated B16-F10 cells. Meanwhile, dodoviscin A could suppress the activity of mushroom tyrosinase in the cell-free assay system and also decrease 3-isobutyl-1-methylxanthine-induced tyrosinase activity and expression of mature tyrosinase protein in B16-F10 cells. Western blotting analysis showed that dodoviscin A inhibited 3-isobutyl-1-methylxanthine and forskolin-induced phosphorylation of the cAMP response element binding protein in B16-F10 cells. These results indicate that dodoviscin A may be a new promising pigmentation-altering agent for cosmetic and therapeutic applications.


Assuntos
Flavonoides/farmacologia , Melaninas/metabolismo , Monofenol Mono-Oxigenase/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sapindaceae/química , Pigmentação da Pele/efeitos dos fármacos , 1-Metil-3-Isobutilxantina/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Flavonoides/química , Flavonoides/isolamento & purificação , Proteínas Fúngicas/efeitos dos fármacos , Proteínas Fúngicas/metabolismo , Humanos , Melanoma Experimental , Camundongos , Modelos Moleculares , Monofenol Mono-Oxigenase/metabolismo , Fosforilação , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Prenilação
7.
J Asian Nat Prod Res ; 14(12): 1103-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23088613

RESUMO

Phytochemical investigation of the stem of Morus notabilis led to the isolation and characterization of 10 compounds of 2-arylbenzofurans (1-10), including two new compounds, (2'R)-2',3'-dihydro-2'-(1-hydroxy-1-methylethyl)-2,6'-bibenzofuran-6,4'-diol (1) and 5,6-dimethoxy-2-(3-hydroxy-5-methoxyphenyl)benzofuran (2). Moracins O (6) and P (10) showed inhibitory effects on mushroom tyrosinase with IC50 values being lower than that of kojic acid.


Assuntos
Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Morus/química , Agaricales/enzimologia , Benzofuranos/química , Medicamentos de Ervas Chinesas/química , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Caules de Planta/química
8.
Bioorg Med Chem Lett ; 22(17): 5428-37, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22858139

RESUMO

In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC(50) less than 1 µM. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Substituição de Aminoácidos , Humanos , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade
9.
J Cell Biochem ; 113(8): 2738-43, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22441938

RESUMO

PDE inhibitors could increase cellular cGMP levels and are used to treat erectile dysfunction as well as pulmonary arterial hypertension. cGMP production was reported to be necessary for UVB-induced melanin synthesis, however, the effect of PDE5 inhibitor on melanin synthesis has not been examined. We found that PDE5 inhibitor (sildenafil or vardenafil) and the cGMP analog 8-CPT-cGMP stimulated CREB phosphorylation, leading to increased tyrosinase expression and melanin synthesis, which was counteracted by KT5823, a selective cGMP-dependent protein kinase (PKG) inhibitor. However, KT5823 did not affect cAMP-elevating agent-mediated melanin synthesis, indicating that KT5823 selectively inhibited cGMP-induced melanin synthesis. This is the first study to find that PDE5 inhibitor can promote melanin synthesis and reveal that PKG-dependent CREB phosphorylation and tyrosinase expression is involved in cGMP-induced melanin synthesis. Our results suggest that PDE5 inhibitor may be beneficial for the treatment of hypopigmentation diseases.


Assuntos
Melaninas/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Linhagem Celular Tumoral , Humanos , Melanoma Experimental/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Chem Biodivers ; 9(2): 394-402, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22344915

RESUMO

Three new isoprenylated flavones, hypargyflavones A-C (1-3, resp.), and one novel stilbene derivative, hypargystilbene A (4), together with seven known compounds, 5-11, were isolated from the stems of Artocarpus hypargyreus Hance. The structures were elucidated by spectroscopic methods. Hypargyflavone A (1), cudraflavone C (8), brosimone I (10), and norartocarpin (11) showed inhibitory effects on pancreatic lipase.


Assuntos
Artocarpus/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Flavonas/isolamento & purificação , Flavonas/farmacologia , Estilbenos/isolamento & purificação , Estilbenos/farmacologia , Inibidores Enzimáticos/química , Flavonas/química , Humanos , Lipase/antagonistas & inibidores , Lipase/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Raízes de Plantas/química , Prenilação , Estilbenos/química
11.
Yao Xue Xue Bao ; 47(12): 1567-74, 2012 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-23460959

RESUMO

BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to-glutamate transition (V600E) that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti-tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Indóis/uso terapêutico , Melanoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas/uso terapêutico , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Vemurafenib
12.
Acta Pharmacol Sin ; 31(11): 1470-7, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21052084

RESUMO

AIM: To test whether pharmacological inhibition of Diacylglycerol acyltransferase 1 (DGAT1) by a small-molecule inhibitor H128 can improve metabolism disorders in leptin receptor-deficient db/db mice. METHODS: To investigate the effect of H128 on intestinal fat absorption,db/db mice were acutely given a bolus of corn oil by gavage. The mice were further orally administered H128 (3 and 10 mg/kg) for 5 weeks. Blood glucose, lipids, insulin, ALT, and AST as well as hepatic triglycerides were measured. The insulin tolerance test was performed to evaluate insulin sensitivity. The expression of genes involved in fatty acid oxidation was detected by RT-PCR. RESULTS: Oral administration of H128 (10 mg/kg) acutely inhibited intestinal fat absorption following a lipid challenge in db/db mice. Chronic treatment with H128 significantly inhibited body weight gain, decreased food intake, and induced a pronounced reduction of serum triglycerides. In addition, H128 treatment markedly ameliorated hepatic steatosis, characterized by decreased liver weight, lipid droplets, and triglyceride content as well as serum ALT and AST levels. Furthermore, H128 treatment increased the expression of the CPT1 and PPARα genes in liver, suggesting that H128 enhanced fatty acid oxidation in db/db mice. However, neither blood glucose nor insulin tolerance was affected by H128 treatment throughout the 5-week experimental period. CONCLUSION: DGAT1 may be an effective therapeutic target for the treatment of obesity, hyperlipidemia and hepatic steatosis.


Assuntos
Compostos de Bifenilo/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Receptores para Leptina/fisiologia , Aumento de Peso/efeitos dos fármacos , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Glicemia/análise , Ingestão de Alimentos/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Ácidos Graxos/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/metabolismo , Hiperlipidemias/enzimologia , Hiperlipidemias/metabolismo , Resistência à Insulina , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Compostos de Fenilureia/química , Compostos de Fenilureia/uso terapêutico , Receptores para Leptina/genética , Triglicerídeos/biossíntese , Triglicerídeos/sangue
13.
Biomed Pharmacother ; 64(9): 647-51, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20888730

RESUMO

GPR40 is a G-protein-coupled receptor specifically expressed in pancreatic islets, which maybe mediate both acute and chronic effects of free fatty acids (FFAs) on ß-cell function. However, it is still a matter of debate whether GPR40 represents a novel therapeutic target for type 2 diabetes. To this aim, we evaluated the effect of DC260126, a small-molecule antagonist of GPR40, on glucose and lipid metabolism in obese Zucker rats. Rats were treated intraperitoneally with 6 mg/kg of DC260126 for 8 weeks. DC260126 could significantly decrease serum insulin levels, improve insulin tolerance and increase Akt phosphorylation levels in liver, suggesting improved insulin sensitivity in DC260126-treated rats. However, DC260126 did not affect food intake, body weight, blood glucose and lipids. Throughout the experimental period, no significant difference in glucose tolerance was observed between the vehicle and DC260126-treated rats. These results indicate that GPR40 antagonists may not be beneficial for the treatment of type 2 diabetes, although GPR40 antagonists could improve insulin tolerance and increase insulin signaling in vivo.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Insulina/sangue , Obesidade/sangue , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Teste de Tolerância a Glucose , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Zucker
14.
Biochem Biophys Res Commun ; 396(4): 1054-9, 2010 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-20471953

RESUMO

Sildenafil is the first oral PDE5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. In the present study, we investigated the effect of sildenafil on adipogenesis in 3T3L1 preadipocytes. Treatment with sildenafil for 8 days significantly promoted adipogenesis characterized by increased lipid droplet and triglyceride content in 3T3L1 cells. Meanwhile, sildenafil induced a pronounced up-regulation of the expression of adipocyte-specific genes, such as aP2 and GLUT4. The results by RT-PCR and Western blotting further showed that sildenafil increased the sequential expression of C/EBP beta, PPAR gamma and C/EBP alpha. Additionally, we found that the other two PDE5 inhibitors (vardenafil and tadalafil) and the cGMP analog 8-pCPT-cGMP also increased adipogenesis. Likewise, 8-pCPT-cGMP could up-regulate the expression of adipogenic and adipocyte-specific genes. Importantly, the PKG inhibitor Rp-8-pCPT-cGMP was able to inhibit both sildenafil and 8-pCPT-cGMP-induced adipogenesis. Furthermore, sildenafil promoted basal and insulin-mediated glucose uptake in 3T3L1 cells, which was counteracted by Rp-8-pCPT-cGMP. These results indicate that sildenafil could promote adipogenesis accompanied by increased glucose uptake through a PKG pathway at least partly.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Insulina/farmacologia , Camundongos , PPAR gama/genética , Purinas/farmacologia , Citrato de Sildenafila , Tionucleotídeos/farmacologia
15.
Bioorg Med Chem Lett ; 20(12): 3675-9, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20471252

RESUMO

In this study, a series of small molecule inhibitors of human FABP4 were identified through virtual screening. Compound 1 is the most potent hit against FABP4 with a selectivity of more than 144-fold preferences over human FABP3. In addition, MD simulation and mutation studies revealed key residues for inhibitory potency and selectivity, which provides a guideline for further drug design against obesity, diabetes and atherosclerosis.


Assuntos
Simulação por Computador , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Sítios de Ligação , Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/química , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Mutação , Obesidade/tratamento farmacológico , Compostos Orgânicos/química , Compostos Orgânicos/farmacologia , Ligação Proteica/genética , Relação Estrutura-Atividade , Especificidade por Substrato
16.
Chem Biodivers ; 6(12): 2209-16, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20020453

RESUMO

Two new isoprenylated 2-arylbenzofurans, artonitidin A (=(2'R)-2',3'-dihydro-2'-(1-hydroxy-1-methylethyl)-5',7-bis(3-methylbut-2-en-1-yl)-2,4'-bi-1-benzofuran-6,6'-diol; and artonitidin B (=5-[6-hydroxy-7-(3-methylbut-2-en-1-yl)-1-benzofuran-2-yl]-4-(3-methylbut-2-en-1-yl)benzene-1,3-diol; together with 14 known compounds, were isolated from the stems of Artocarpus nitidus Trec. The structures were elucidated by spectroscopic methods. Norartocarpin, cudraflavone C, brosimone I, artotonkin, albanin A, and artopetelin M showed inhibitory effects on pancreatic lipase with IC(50) values ranging from 1.8+/-0.1 to 63.8+/-3.6 microM.


Assuntos
Artocarpus/química , Benzofuranos/química , Lipase/metabolismo , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Lipase/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Conformação Molecular , Caules de Planta/química , Prenilação
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