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1.
Bioorg Chem ; 120: 105600, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35078048

RESUMO

Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as dual PPARα/γ partial agonists with potency in the nanomolar range. In vitro and in vivo assays revealed that the lead compound (E)-4-styrylphenoxy-propanamide (5b) removed 14C-cholesterol from the foam cells through apolipoprotein A-I and High-Density Lipoprotein-2. In the high-fat diet-induced obesity mouse model, the oral administration of compound 5b increased HDL levels, paraoxonase-1 activity, and insulin sensitivity, and decreased glucose levels. Moreover, the adipogenesis pathway and triglyceride accumulation slightly changed in the adipocyte cells upon treatment with compound 5b, without affecting the body weight and adipose tissue in obese mice. Compound 5b did not affect the plasma levels of hepatic and renal injury biomarkers. Thus, stilbene-based compound 5b is a promising prototype for developing novel candidates to treat dyslipidemia and diabetes.


Assuntos
Diabetes Mellitus , Dislipidemias , Estilbenos , Adipogenia , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/tratamento farmacológico , Glucose/metabolismo , Lipoproteínas HDL/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , Estilbenos/uso terapêutico
2.
Molecules ; 26(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921198

RESUMO

Cyclooxygenase (COX) and lipoxygenase (LOX) are key targets for the development of new anti-inflammatory agents. LOX, which is involved in the biosynthesis of mediators in inflammation and allergic reactions, was selected for a biochemical screening campaign to identify LOX inhibitors by employing the main natural product library of Brazilian biodiversity. Two prenyl chalcones were identified as potent inhibitors of LOX-1 in the screening. The most active compound, (E)-2-O-farnesyl chalcone, decreased the rate of oxygen consumption to an extent similar to that of the positive control, nordihydroguaiaretic acid. Additionally, studies on the mechanism of the action indicated that (E)-2-O-farnesyl chalcone is a competitive LOX-1 inhibitor. Molecular modeling studies indicated the importance of the prenyl moieties for the binding of the inhibitors to the LOX binding site, which is related to their pharmacological properties.


Assuntos
Chalconas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores de Lipoxigenase/farmacologia , Modelos Moleculares , Prenilação , Chalconas/química , Concentração Inibidora 50 , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/química , Simulação de Acoplamento Molecular , Consumo de Oxigênio/efeitos dos fármacos
3.
J Med Chem ; 67(11): 8609-8629, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38780468

RESUMO

Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.


Assuntos
Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Pteridinas , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pteridinas/farmacologia , Pteridinas/química , Pteridinas/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/metabolismo , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase 1 épsilon/metabolismo , Linhagem Celular Tumoral
5.
J Nat Prod ; 74(4): 776-81, 2011 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-21381705

RESUMO

Four new clerodane diterpenes, casearupestrins A-D (1-4), were isolated from the leaves of Casearia rupestris. Compounds 1 and 4 were acetylated to yield 2,7-di-O-acetylcasearupestrin A (5) and 2,6-di-O-acetylcasearupestrin D (6). All compounds were evaluated for cytotoxicity against a small panel of human cancer cell lines. Casearupestrin A (1) exhibited the most potent activity against MDA/MB-435 (human melanoma) and SF-295 (human glioblastoma) cells, superior to that of the standard drug doxorubicin.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Casearia/química , Diterpenos Clerodânicos/isolamento & purificação , Diterpenos Clerodânicos/farmacologia , Antineoplásicos Fitogênicos/química , Brasil , Diterpenos Clerodânicos/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Folhas de Planta/química
6.
Future Microbiol ; 15: 21-33, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32043361

RESUMO

Aim: This study aimed to evaluate the activity of 2'-hydroxychalcone-loaded in nanoemulsion (NLS + 2'chalc), the cytotoxic effect and toxicity against Paracoccidioides brasiliensis and Paracoccidioides lutzii using a zebrafish model. Materials & methods: Preparation and physical-chemical characterization of nanoemulsion (NLS) and NLS + 2'chalc were performed. MIC and minimum fungicide concentration, cytotoxicity and toxicity were also evaluated in the Danio rerio model. Results: NLS + 2'chalc showed fungicidal activity against Paracoccidioides spp. without cytotoxicity in MRC5 and HepG2 lines. It also had high selectivity index values and no toxicity in the zebrafish model based on MIC values. Conclusion: NLS + 2'chalc is a potential new alternative treatment for paracoccidioidomycosis.


Assuntos
Antifúngicos/farmacologia , Chalconas/farmacologia , Paracoccidioides/efeitos dos fármacos , Animais , Linhagem Celular , Chalconas/química , Emulsões/farmacologia , Fibroblastos/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Modelos Animais , Nanopartículas , Paracoccidioidomicose/microbiologia , Peixe-Zebra
7.
ACS Med Chem Lett ; 10(9): 1266-1271, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531195

RESUMO

Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.

8.
Rev. bras. farmacogn ; 27(6): 785-787, Nov.-Dec. 2017. graf
Artigo em Inglês | LILACS | ID: biblio-1042255

RESUMO

ABSTRACT Chemical investigation of the leaves of Casearia gossypiosperma Briq., Salicaceae, led to the isolation of two known flavonoids, (+)-taxifolin and quercetin, the leaves of Casearia decandra Jacq. have afforded hydroquinone, the leaves of Casearia rupestris Eichler and Casearia lasiophylla Eichler have afforded a diterpene, (E)-phytol, and the leaves of C. rupestris and Casearia obliqua Spreng. have afforded sitosterol. The twigs of Casearia lasiophylla Eichler led to the isolation of two compounds (+)-pinoresinol, and N-trans-feruloyltyramine, and the twigs of C. obliqua have afforded N-trans-feruloyltyramine, N-trans-cumaroyltyramine, and cinamic acid. This is the first report of the compounds (+)-taxifolin, quercetin, hydroquinone, (+)-pinoresinol and N-trans-cumaroyltyramine from the Casearia genus.

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