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1.
J Med Chem ; 65(3): 1961-1978, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35089724

RESUMO

Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 ∼ 100 nM to 10 µM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.


Assuntos
Ácidos Anacárdicos/farmacologia , Anacardium/química , Nozes/química , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Células 3T3-L1 , Ácidos Anacárdicos/síntese química , Ácidos Anacárdicos/metabolismo , Ácidos Anacárdicos/farmacocinética , Animais , Desenho de Fármacos , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , PPAR alfa/química , PPAR delta/química , PPAR gama/química , Domínios Proteicos , Peixe-Zebra
2.
Neurochem Int ; 146: 105021, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741413

RESUMO

Benzodiazepines are commonly used to treat disorders of the central nervous system, including anxiety. However, due to their adverse effects, there is a continuing interest in discovering new safe and effective drugs. Marine natural products have emerged as a prolific source of bioactive nitrogenated compounds. Aiming to discover new biologically active natural compounds, the marine sponge Aplysina fulva, a nitrogen-bearing heterocyst producer, was investigated. The main isolated compounds (4, 6, and 9) were evaluated on adult zebrafish (Danio rerio). A group of fishes (n = 6) was preliminarily subjected to acute toxicity, and open field tests using 0.1, 0.5, and 1.0 mg/mL (v. o.) of those compounds was performed. The anxiolytic effect was further investigated in the light/dark assay based on the locomotor response at zebrafish. Interactions through the GABAergic system were investigated using flumazenil, a silent modulator of GABA receptors. To improve the results, a study of molecular docking using the GABAA receptor also was performed. Based on the results, the bromotyrosine derivative compounds 4, 6, and 9 exhibited anxiolytic-like effects mediated by the GABAergic system.


Assuntos
Ansiolíticos/farmacologia , Produtos Biológicos/farmacologia , Brometos/farmacologia , Moduladores GABAérgicos/farmacologia , Receptores de GABA-A/metabolismo , Fatores Etários , Animais , Ansiolíticos/química , Ansiolíticos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Brometos/química , Brometos/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Moduladores GABAérgicos/química , Moduladores GABAérgicos/isolamento & purificação , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Poríferos , Estrutura Secundária de Proteína , Receptores de GABA-A/química , Peixe-Zebra
3.
Fitoterapia ; 149: 104760, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33075410

RESUMO

Three new caged polyprenylated benzophenone derivatives named burlemarxiones D-F (1-3) were isolated from the hexane extract of Clusia burle-marxii trunks. Burlemarxione D (1) contains the tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton also observed for burlemarxione A, its probable immediate precursor. However, two additional rings are formed to produce an unprecedented complex-caged core skeleton. These additional rings could be formed by a radical cyclization reaction of one prenyl group at C-5 with C-1 and C-33, followed by oxidative dehydrogenation (rearomatization) or by an intramolecular [4 + 2] radical cycloaddition (Diels-Alder reaction), followed by an enolization reaction (rearomatization). Burlemarxiones E and F were isolated after methylation with diazomethane that was necessary to avoid the interconversion of the pair of ß-diketones in tautomeric equilibrium. The proposed biosynthetic pathway for burlemarxiones D-F involves the condensation of either lavandulyl pyrophosphate or 2-(1-methylvinyl)-hexa-5-enyl pyrophosphate with the acylphloroglucinol derivative 6-benzoyl-5-hydroxy-5-cyclohexen-1,3-dione, followed by consecutive prenylation reactions. Therefore, Clusia burle-marxii reinforces the claim that the genus Clusia is an important source of sophisticated caged polyprenylated benzophenone derivatives.


Assuntos
Benzofenonas/química , Clusia/química , Benzofenonas/isolamento & purificação , Brasil , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Prenilação
4.
Food Res Int ; 138(Pt A): 109759, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33292941

RESUMO

Egletes viscosa is a Brazilian medicinal herb consumed as flower bud tea due to its gastroprotective properties. This plant possesses two essential oil-based chemical varieties: trans-pinocarveyl acetate-rich chemotype A and cis-isopinocarveyl acetate- rich chemotype B. Therefore, we developed two simple, fast and reliable methods for discrimination of E. viscosa chemotypes using NIR and 1H qNMR spectroscopies combined with the chemometrics tools (iPLS and PLS-DA). Both methods showed high sensitivity, precision and specificity in the cross-validation tests. The NIR method has the advantages of being non-destructive and analyzable by portable devices, enabling its application for field and industrial evaluations. Meanwhile, the 1H qNMR method allows the quantification of the bioactive components ternatin, tanabalin, and centipedic acid. These aforementioned compounds were found higher in the chemotype A. Accordingly, our methods showed to be complimentary approaches for authenticity and/or quality control of E. viscosa-derived raw materials and herbal products.


Assuntos
Asteraceae , Óleos Voláteis , Plantas Medicinais , Brasil , Extratos Vegetais
5.
Sci Rep ; 10(1): 22283, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335138

RESUMO

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression.


Assuntos
Anexina A1/genética , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piper/química , Piperidonas/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias/patologia , Piperidonas/química , Microambiente Tumoral/efeitos dos fármacos
6.
Int J Biol Macromol ; 165(Pt A): 1055-1065, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987080

RESUMO

Due to the limited options for topical management of skin cancer, this study aimed at developing and evaluating nanoemulsions (NE) for topical delivery of the cytotoxic agent piplartine (piperlongumine). NEs were modified with chitosan or sodium alginate, and the effects on the physicochemical properties, piplartine delivery and formulation efficacy were evaluated. The nanoemulsion droplets displayed similar size (96-112 nm), but opposite charge; the polysaccharides improved piplartine penetration into and across the skin (1.3-1.9-fold) in a similar manner, increasing the ratio "drug in the skin/receptor phase" by 1.4-1.5-fold compared to the plain NE and highlighting their relevance for cutaneous localization. Oleic acid addition to the chitosan-containing NE further increased drug penetration (~1.9-2.0-fold), as did increases in drug content from 0.5 to 1%. The cytotoxicity of piplartine was ~2.8-fold higher when the drug was incorporated in the chitosan-containing NE compared to its solution (IC50 = 14.6 µM) against melanoma cells. The effects of this nanocarrier on 3D melanoma tissues were concentration-related; at 1%, piplartine elicited marked epidermis destruction. These results support the potential applicability of the chitosan-modified nanoemulsion containing piplartine as a new strategy for local management of skin cancer.


Assuntos
Emulsões/química , Melanoma/tratamento farmacológico , Nanopartículas/química , Neoplasias Cutâneas/tratamento farmacológico , Alginatos/química , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Citotoxinas/química , Emulsões/farmacologia , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Piperidonas/química , Piperidonas/farmacologia , Neoplasias Cutâneas/patologia
7.
Phytochemistry ; 178: 112458, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32888670

RESUMO

Six previously undescribed tropane alkaloids, designated as erythrobezerrines A-F, were isolated from the EtOH extract from the stem bark of Erythroxylum bezerrae Plowman. Their structures were elucidated based on the interpretation of the NMR and MS data and in some instances, confirmed by X-ray diffraction analysis. The cytotoxicity of the isolated compounds was evaluated against the cancer cell lines L929, PC-3, HCT-116, SNB-19 and NCI-H460, but only erythrobezerrine C showed moderate activity with IC50 values of 3.38 and 5.43 µM for HCT-116 and NCI-H460, respectively.


Assuntos
Erythroxylaceae , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Casca de Planta , Tropanos
8.
Fitoterapia ; 138: 104357, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521701

RESUMO

Three new 3-hydroxy-N-methyl-2-oxindole (1 and 2) and 4-hydroxy-pyran-2-one (3) derivatives, along with the known 3-hydroxy-N-methyl-2-oxindole (4) and 6-methoxy-N-methylisatin (5) were isolated from a marine Salinispora arenicola strain from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the new compounds were elucidated by a combination of spectroscopic (1D and 2D NMR and HR-ESIMS) data, including single-crystal X-ray diffraction analysis for 2 and 3. Compounds 1 to 5 were assayed for their antimicrobial properties, but only 4 and 5 were active against Enterococcus faecalis with MIC value of 15.6 µg/mL.


Assuntos
Antibacterianos/farmacologia , Sedimentos Geológicos/microbiologia , Micromonosporaceae/química , Oxindóis/farmacologia , Antibacterianos/isolamento & purificação , Brasil , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxindóis/isolamento & purificação , Água do Mar/microbiologia
9.
Fitoterapia ; 138: 104346, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465815

RESUMO

Three new polyprenylated benzophenone derivatives (1-3) were identified in the hexane extract of Clusia burle-marxii trunks, through the isolation and structural elucidation of their methyl derivatives, along with two known polyprenylated benzophenone derivatives sampsonine N (4) and obdeltifolione C (5). Burlemarxiones A (1) and B (2) show an unprecedent tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton. These compounds are a pair of ß-diketones in tautomeric equilibrium, whereas isonemorosonol (3) is the respective ß-diketone pair in tautomeric equilibrium with nemorosonol. Burlemarxione A methyl derivative (1a) and sampsonine N exhibited strong in vitro cytotoxic activity against GL-15 glioblastoma-derived human cell line.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/farmacologia , Clusia/química , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofenonas/isolamento & purificação , Brasil , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
10.
J Nat Prod ; 82(7): 1831-1838, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31313922

RESUMO

Salinaphthoquinones A-E (1-5) were isolated from a marine Salininispora arenicola strain, recovered from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the compounds were elucidated using a combination of spectroscopic (NMR, IR, HRESIMS) data, including single-crystal X-ray diffraction analysis. A plausible biosynthetic pathway for 1-5 is proposed. Compounds 1 to 4 displayed moderate activity against Staphylococcus aureus and Enterococcus faecalis with MIC values of 125 to 16 µg/mL.


Assuntos
Antibacterianos/farmacologia , Sedimentos Geológicos/química , Micromonosporaceae/química , Naftoquinonas/farmacologia , Água do Mar/química , Antibacterianos/química , Brasil , Sedimentos Geológicos/microbiologia , Estrutura Molecular , Naftoquinonas/química , Água do Mar/microbiologia
11.
Int J Pharm ; 567: 118460, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247278

RESUMO

As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5 ±â€¯1.2 nm. Heating the aqueous phase to 50 °C enabled sonication time reduction from 20 to 10 min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120 h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60 days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Dioxolanos/administração & dosagem , Glândulas Mamárias Animais/metabolismo , Nanopartículas/administração & dosagem , Piperidonas/administração & dosagem , Adesividade , Animais , Antineoplásicos Fitogênicos/química , Galinhas , Quitosana/administração & dosagem , Quitosana/química , Membrana Corioalantoide/efeitos dos fármacos , Dioxolanos/química , Vias de Administração de Medicamentos , Emulsões , Feminino , Glicerol/administração & dosagem , Glicerol/química , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Nanopartículas/química , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Piperidonas/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Ratos Wistar , Pele/química , Suínos
12.
Pain Rep ; 4(6): e791, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31984296

RESUMO

Introduction: In recent decades, several researches have been conducted in search of new analgesics that do not present the side effects of opioids. In this context, animal venoms contain natural painkillers that have been used for the development of new analgesics. Objective: The aims of this study were to evaluate the antinociceptive effects of telocinobufagin (TCB), a bufadienolide isolated from Rhinella jimi venom, in murine acute pain models, and to verify the participation of the opioid system in these effects. Methods: TCB was purified from R. jimi venom by high-performance liquid chromatography, and its structure was confirmed by spectrometric techniques. TCB was administered intraperitoneally (i.p.) (0.062, 0.125, 0.25, 0.5, and 1 mg·kg-1) and orally (p.o.) (0.625, 1.125, 2.5, 5, and 10 mg·kg-1) in mice, which were then subjected to pain tests: acetic acid-induced writhing, formalin, tail-flick, and hot-plate. Involvement of the opioid system in TCB action was evaluated by naloxone i.p. injected (2.5 mg·kg-1) 20 minutes before TCB administration. In addition, the TCB action on the µ, δ, and κ opioid receptors was performed by radioligand binding assays. Results: In all the tests used, TCB showed dose-dependent antinociceptive activity with more than 90% inhibition of the nociceptive responses at the doses of 1 mg·kg-1 (i.p.) and 10 mg·kg-1 (p.o.). Naloxone did not alter the effect of TCB. In addition, TCB did not act on the µ, δ, and κ opioid receptors. Conclusion: The results suggest that TCB may represent a novel potential nonopioid therapeutic analgesic for treatment of acute pains.

13.
J Pharm Pharmacol ; 70(6): 787-796, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29490425

RESUMO

OBJECTIVES: Aspidosperma species are used for several diseases, especially for malaria in Brazil. Although the genus is object of pharmacological studies, almost none are found on Aspidosperma pyrifolium. We investigate neuroprotective, antioxidant and anti-inflammatory properties of the APSE-Aq fraction (benzoic acid glycosylated derivative) on Parkinson's disease model. METHODS: Male Wistar rats were subjected to a 6-hydroxydopamine injection into the right striatum and treated or not with APSE-Aq (100 or 200 mg/kg, p.o.). The sham-operated group was injected with saline. Two weeks later, animals were subjected to behavioural, neurochemical and immunohistochemical evaluation. The data were analysed by ANOVA and Tukey test. KEY FINDINGS: The APSE-Aq-treated group shows a partial recovery of behavioural changes as compared with the untreated-6-hydroxydopamine group. A partial recovery was also observed in nitrite contents and lipid peroxidation. APSE-Aq treatments significantly reversed decreases in striatal dopamine and metabolites in the untreated 6-hydroxydopamine group. Immunostainings for markers as tyrosine hydroxylase and dopamine transporter decreased in the untreated 6-hydroxydopamine group and values recovered after APSE-Aq treatments. Similar data were seen for TNF-alpha. CONCLUSION: APSE-Aq presents neuroprotective, antioxidant and anti-inflammatory activities. Considering that APSE-Aq is chemically related to salicylic acid, it may act on similar targets.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aspidosperma/química , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nitritos/metabolismo , Oxidopamina/metabolismo , Extratos Vegetais/química , Ratos , Sementes/química , Fator de Necrose Tumoral alfa/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
14.
Fitoterapia ; 123: 65-72, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28964874

RESUMO

Five new meroterpenoid compounds designed as rel-10ß,11ß-epoxy-2,11-dimethoxy-8α-hydroxy-8aß-methyl-5α,6,7,8,8a,9,10,10aß-octahydro-1,4-anthracendione (1), rel-10ß,11ß-epoxy-8α,5-dihydroxy-2-methoxy-8aß-methyl-5,6,7,8,8a,9,10,10aß-octahydro -1.4-anthracendione (2), rel-1,4,8α-trihydroxy-5-furanyl-2-methoxy-8aß-methyl-6,7,8, 8a,9,10-hexahydro-10-anthracenone (3), rel-10α,11α-epoxy-8α,11ß-dihydroxy-8aß-methyl-5ß,6,7,8,8a,9,10,10aß-octahydro-1,4-anthracenediol (4) and rel-1,4,8α-trihydroxy-5-carboxyethyl-2-methoxy-8aß-methyl-6,7,8,8a,9,10-hexahydro-10-anthra-cenone (5), besides seven (6-12) known compounds were isolated from the heartwood and sapwood ethanol extracts of Cordia oncocalyx. Moreover, the main isolated compounds were screened using the electrically driven mice vas deferens bioassay, which has a rich pharmacological receptors diversity.


Assuntos
Benzoquinonas/química , Cordia/química , Hidroquinonas/química , Contração Muscular/efeitos dos fármacos , Terpenos/química , Animais , Benzoquinonas/isolamento & purificação , Hidroquinonas/isolamento & purificação , Técnicas In Vitro , Masculino , Camundongos , Estrutura Molecular , Terpenos/isolamento & purificação , Ducto Deferente/efeitos dos fármacos
15.
Molecules ; 22(10)2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28946655

RESUMO

Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic culture and biofilms. VIO showed excellent antimicrobial activity in inhibiting and killing S. aureus in planktonic cultures and biofilm formation. The minimum bactericidal concentration (5 µg/mL) of VIO caused the death of S. aureus after 3-4 h of exposure and the minimum inhibitory concentration (1.25 µg/mL) of VIO inhibited bacterial growth within the first 8 h of contact. Biofilm formation was also strongly inhibited by VIO (1.25 µg/mL), in contrast to the higher resistance verified for S. aureus in mature biofilm (40 µg/mL). The high bacterial metabolic activity favored VIO activity; however, the good activity observed during phases of reduced metabolism indicates that VIO action involves more than one mechanism. Thus, VIO is a promising molecule for the development of an antimicrobial drug for the eradication of S. aureus infections.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Indóis/farmacologia , Plâncton/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Testes de Sensibilidade Microbiana
16.
Biochim Biophys Acta Gen Subj ; 1861(8): 1943-1950, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28506883

RESUMO

Cardiotonic steroids (CS) are known as modulators of sodium and water homeostasis. These compounds contribute to the excretion of sodium under overload conditions due to its natriuretic property related to the inhibition of the renal Na+/K+-ATPase (NKA) pump α1 isoform. NHE3, the main route for Na+ reabsorption in the proximal tubule, depends on the Na+ gradient generated by the NKA pump. In the present study we aimed to investigate the effects of marinobufagin (MBG) and telocinobufagin (TBG) on the renal function of isolated perfused rat kidney and on the inhibition of NKA activity. Furthermore, we investigated the mechanisms for the cardiotonic steroid-mediated natriuretic effect, by evaluating and comparing the effects of bufalin (BUF), ouabain (OUA), MBG and TBG on NHE3 activity in the renal proximal tubule in vivo. TBG significantly increased GFR, UF, natriuresis and kaliuresis in isolated perfused rat kidney, and inhibits the activity of NKA at a much higher rate than MBG. By stationary microperfusion technique, the perfusion with BUF, OUA, TBG or MBG promoted an inhibitory effect on NHE3 activity, whereas BUF was the most effective agent, and demonstrated a dose-dependent response, with maximal inhibition at 50nM. Furthermore, our data showed the role of NKA-Src kinase pathway in the inhibition of NHE3 by CS. Finally, a downstream step, MEK1/2-ERK1/2 was also investigated, and, similar to Src inhibition, the MEK1/2 inhibitor (U0126) suppressed the BUF effect. Our findings indicate the involvement of NKA-SRc-Kinase-Ras-Raf-ERK1/2 pathway in the downregulation of NHE3 by cardiotonic steroids in the renal proximal tubule, promoting a reduction of proximal sodium reabsorption and natriuresis.


Assuntos
Bufanolídeos/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Rim/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Técnicas In Vitro , Túbulos Renais Proximais/metabolismo , Masculino , Ratos , Ratos Wistar , Trocador 3 de Sódio-Hidrogênio , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/fisiologia , Quinases da Família src/fisiologia
18.
Phytochemistry ; 130: 321-7, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27498045

RESUMO

Seven withanolides, including four previously unknown, were isolated from the acetone and ethanol extracts of cultivated specimens of Acnistus arborescens. These four compounds were identified as rel-(18R,22R)-5ß,6ß:18ß,20-diepoxy-3ß,18α-dimethoxy-4ß-hydroxy-1-oxowith-24-enolide, rel-(20R,22R)-5ß,6ß-epoxy-4ß,16α,20-trihydroxy-1-oxowitha-2,24dienolide, rel-(20R,22R)-16α-acetoxy-6α-chloro-4ß,5ß,20-trihydroxy-1-oxowitha-2,24-dienolide and rel-(20R,22R)-16α-acetoxy-20-hydroxy-1-oxowitha-2,5,24-trienolide. Their structures were elucidated by interpretation of spectroscopic data (1D and 2D NMR), HRESIMS experiments and comparison with published data for similar compounds. Cytotoxicity of the isolated compounds was evaluated against a panel of four tumor cell lines (HL-60, HCT-116, SF-268 and PANC-1). Withanolide D was the most active, with an IC50 value in the range of 0.3-1.7 µM, rel-(18R,22R)-5ß,6ß:18ß,20-diepoxy-3ß,18α-dimethoxy-4ß-hydroxy-1-oxowith-24-enolide and rel-(20R,22R)-5ß,6ß-epoxy-4ß,16α,20-trihydroxy-1-oxowitha-2,24dienolide were moderately active, while all the others were non-cytotoxic.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Solanaceae/química , Vitanolídeos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/química , Células HCT116 , Células HL-60 , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Estereoisomerismo , Vitanolídeos/química , Vitanolídeos/farmacologia
19.
Chem Biodivers ; 13(9): 1149-1157, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27454443

RESUMO

Saint Peter and Saint Paul's Archipelago is a collection of 15 islets and rocks remotely located in the equatorial Atlantic Ocean. In this particular site, the present project intended to assess the biodiversity and biotechnological potential of bacteria from the actinomycete group. This study presents the first results of this assessment. From 21 sediment samples, 268 strains were isolated and codified as BRA followed by three numbers. Of those, 94 strains were grown in liquid media and submitted to chemical extractions with AcOEt (A), BuOH (B), and MeOH (M). A total of 224 extracts were screened for their cytotoxic activity and 41 were significantly active against HCT-116 cancer cells. The obtained IC50 values ranged from 0.04 to 31.55 µg/ml. The HR-LC/MS dereplication analysis of the active extracts showed the occurrence of several known anticancer compounds. Individual compounds, identified using HR-MS combined with analysis of the AntiMarin database, included saliniketals A and B, piericidins A and C and glucopiericidin A, staurosporine, N-methylstaurosporine, hydroxydimethyl-staurosporine and N-carbamoylstaurosporine, salinisporamycin A, and rifamycins S and B. BRA-199, identified as Streptomyces sp., was submitted to bioassay-guided fractionation, leading to isolation of the bioactive piericidins A and C, glucopiericidin, and three known diketopiperazines, cyclo(l-Phe-trans-4-OH-l-Pro), cyclo(l-Phe-l-Pro), and cyclo(l-Trp-l-Pro).


Assuntos
Actinobacteria/química , Actinobacteria/isolamento & purificação , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Sedimentos Geológicos/microbiologia , Antineoplásicos Fitogênicos/química , Brasil , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Conformação Molecular , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 122: 601-610, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27448917

RESUMO

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Desenho de Fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Técnicas de Química Sintética , Clonagem Molecular , Cricetinae , Cricetulus , Humanos , Masculino , Simulação de Acoplamento Molecular , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Piperazinas/química , Piperazinas/metabolismo , Conformação Proteica , Ratos , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/genética , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
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