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1.
Bioorg Chem ; 116: 105315, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34496319

RESUMO

Chalcones and their derivatives have been described as promising compounds with antiproliferative activity against leukemic cells. This study aimed to investigate the cytotoxic effect of three synthetic chalcones derived from 1-naphthylacetophenone (F07, F09, and F10) in acute leukemia cell lines (K562 and Jurkat) and examine the mechanisms of cell death induced by these compounds. The three compounds were cytotoxic to K562 and Jurkat cells, with IC50 values ranging from 1.03 to 31.66 µM. Chalcones induced intrinsic and extrinsic apoptosis, resulting in activation of caspase-3 and DNA fragmentation. F07, F09, and F10 were not cytotoxic to human peripheral blood mononuclear cells, did not produce any significant hemolytic activity, and did not affect platelet aggregation after ADP stimulation. These results, combined with calculations of molecular properties, suggest that chalcones F07, F09, and F10 are promising molecules for the development of novel antileukemic drugs.


Assuntos
Acetofenonas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Acetofenonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Bioorg Chem ; 114: 105157, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328855

RESUMO

A new library of hybrid compounds that combine the functional parts of glibenclamide and pioglitazone was designed and developed. Compounds were screened for their antihyperglycemic effects on the glucose tolerance curve. This approach provided a single molecule that optimizes the pharmacological activities of two drugs used for the treatment of diabetes mellitus type 2 (DM2) and that have distinct biological activities, potentially minimizing the adverse effects of the original drugs. From a total of 15 compounds, 7 were evaluated in vivo; the compound 2; 4- [2- (2-phenyl-4-oxo-1,3-thiazolidin-3-yl) ethyl] benzene-1-sulfonamide (PTEBS) was selected to study its mechanism of action on glucose and lipid homeostasis in acute and chronic animal models related to DM2. PTEBS reduced glycemia and increased serum insulin in hyperglycemic rats, and elevated in vitro insulin production from isolated pancreatic islets. This compound increased the glycogen content in hepatic and muscular tissue. Moreover, PTEBS stimulated the uptake of glucose in soleus muscle through a signaling pathway similar to that of insulin, stimulating translocation and protein synthesis of glucose transporter 4 (GLUT4). PTEBS was effective in increasing insulin sensitivity in resistance rats by stimulating increased muscle glucose uptake, among other mechanisms. In addition, this compound reduced total triglycerides in a tolerance test to lipids and reduced advanced glycation end products (AGES), without altering lactate dehydrogenase (LDH) activity. Thus, we suggest that PTEBS may have similar effects to the respective prototypes, which may improve the therapeutic efficacy of these molecules and decrease adverse effects in the long-term.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Pioglitazona/farmacologia , Animais , Relação Dose-Resposta a Droga , Glibureto/química , Homeostase/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Resistência à Insulina , Estrutura Molecular , Pioglitazona/química , Ratos , Relação Estrutura-Atividade
3.
Hematol Oncol Stem Cell Ther ; 14(1): 51-64, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32763229

RESUMO

The present study aimed to investigate the cytotoxic effect of 38 new thiosemicarbazone derivatives on hematological neoplastic cells lines and to select the most effective compounds to investigate the main molecular mechanisms involved in cell death. Cytotoxicity screening on Daudi and Jurkat cells revealed that only compound 1b met the selection criteria; therefore, it was chosen for further investigation. Cell viability of Daudi, Jurkat, Molt-4, Namalwa, K562, and MM.1S cell lines decreased in a concentration- and time-dependent manner after compound1b incubation; nevertheless the compound neither caused significant hemolysis nor reduction in peripheral blood mononuclear cell viability. Although no changes were observed on cell cycle or Ki-67 expression, compound1b induced apoptotic-like cell death with mitochondrial involvement, Bax/Bcl-2 inversion, AIF release, survivin inhibition, and caspase-3 activation in both Daudi and Jurkat cells. Furthermore, the compound reduced NFκB expression in Jurkat cells. In Daudi cells, compound1b also decreased CHOP, Akt, pAkt, and MAPK/ERK2 expression, thereby suggesting modulation of UPR, PI3K/Akt/mTOR, and MAPK/ERK signaling pathways. Finally, the compound was able to reduce the cell viability of samples collected from patients with different lymphoid neoplasms subtypes, showing that thiosemicarbazones derivatives could be used in the development of new drugs with anticancer activity.


Assuntos
Antineoplásicos , Citotoxinas , Leucemia , Linfoma , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Tiossemicarbazonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Células Jurkat , Células K562 , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
4.
J Cell Physiol ; 234(7): 10138-10147, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30417369

RESUMO

AIM: To investigate the mechanism of action of sulfonyl(thio)urea derivative (SD) on glycemia and on insulin secretion in pancreatic islets. METHODS: Wistar rats were divided into hyperglycemic control group, rats received 4 g/kg body weight glucose plus sitagliptin 10 mg/kg (p.o.); hyperglycemic plus SD 10 mg/kg (p.o.); hyperglycemic plus SD plus sitagliptin. Blood was collected before glucose overloading (zero time), and at 15, 30, 60, and 180 min after glucose, from the afore mentioned groups for glycemia and glucagon-like peptide 1 (GLP-1) measurements and intestinal disaccharidases activity. Pancreatic islets were isolated for the calcium influx and insulin secretion in in vitro studies. RESULTS: SD reduced glycemia and increased GLP-1 secretion, while inhibited sucrase and lactase activity. This SD (1.0 and 10.0 µM) stimulated calcium influx in a similar percentile to that of glibenclamide, and in a nonsynergic manner. In addition, the trigger effect of SD on calcium influx was through the K+ -ATP-dependent channels, and partially by activating voltage-dependent K + channels and voltage-dependent calcium channels. Furthermore, SD-stimulated Na + and Ca 2+ entry, induced by the transient receptor potential ankyrin 1 and by modulation of Na + /Ca 2+ exchange. The activation of these pathways by SD culminated in in vitro insulin secretion, reinforcing the critical role of K + -ATP channels in the secretagogue effect of SD. CONCLUSIONS: SD diminish glycemia by inducing GLP-1 secretion and inhibiting disaccharidases. To our knowledge, this is the first report of an insulin secretagogue effect of SD that is mediated by potassium and calcium, as well as sodium, signal transduction.


Assuntos
Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Compostos de Sulfonilureia/farmacologia , Animais , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hiperglicemia/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismo
5.
Bioorg Med Chem ; 27(2): 375-382, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30579801

RESUMO

Malignant neoplasms are one of the leading causes of death worldwide and hematologic malignancies, including acute leukemia (AL) is one of the most relevant cancer types. Current available chemotherapeutics are associated with high morbidity and mortality rates, therefore, the search for new molecules with antitumor activity, specific and selective for neoplastic cells, became a great challenge for researchers in the oncology field. As pyrazolines stand out in the literature for their great variety of biological activities, the aim of this study was to synthesize and evaluate the antileukemic activity of five new pyrazoline derivatives. All pyrazolines showed adequate physicochemical properties for a good oral bioavailability. The two unpublished and most effective pyrazoline derivatives have been selected for further experiments. These compounds are highly selective for leukemic cells when compared to non-neoplastic cells and did not cause lysis on human red blood cells. Additionally, selected pyrazolines induced cell cycle arrest at G0/G1 phase and decreased cell proliferation marker KI67. Apoptotic cell death induced by selected pyrazolines was confirmed by morphological analysis, assessment of phosphatidylserine residue exposure and DNA fragmentation. Several factors indicate that both intrinsic and extrinsic apoptosis occurred. These were: increased FasR expression; the predominance of Bax in relation to Bcl-2; the loss of mitochondrial membrane potential; AIF release; decreased expression of survivin (an antiapoptotic protein); and the activation of caspase-3. The selected pyrazolines were also found to be cytotoxic against neoplastic cells collected from the peripheral blood and bone marrow of patients with different subtypes of acute leukemia.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pirazóis/farmacologia , Doença Aguda , Antineoplásicos/síntese química , Antineoplásicos/química , Fator de Indução de Apoptose/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Survivina/metabolismo , Proteína X Associada a bcl-2/metabolismo
6.
Bioorg Med Chem ; 26(21): 5742-5750, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389409

RESUMO

Mycobacterium tuberculosis secretes two protein tyrosine phosphatases as virulence factors, PtpA and PtpB. Inhibition studies of these enzymes have shown significant attenuation of the M. tuberculosis growth in vivo. As PtpA mediates many effects on the regulation of host signaling ensuring the intracellular survival of the bacterium we report, for the first time, thiosemicarbazones as potential novel class of PtpA inhibitors. Several compounds were synthesized and biologically evaluated, revealing interesting results. Enzyme kinetic assays showed that compounds 5, 9 and 18 are non-competitive inhibitors of PtpA, with Ki values ranging from 1.2 to 5.6 µM. Modeling studies clarified the structure-activity relationships observed in vitro and indicated a possible allosteric binding site in PtpA structure. To the best of our knowledge, this is the first disclosure of potent non-competitive inhibitors of PtpA with great potential for future studies and development of analogues.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Tiossemicarbazonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Tirosina Fosfatases/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química
7.
Can J Physiol Pharmacol ; 95(5): 548-563, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28177693

RESUMO

Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Leucemia/patologia , Pirazóis/química , Pirazóis/farmacologia , Antineoplásicos/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Fragmentação do DNA/efeitos dos fármacos , Humanos , Células Jurkat , Células K562 , Pirazóis/farmacocinética , Transdução de Sinais/efeitos dos fármacos
8.
Curr Drug Targets ; 18(6): 641-650, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27316908

RESUMO

Glibenclamide is widely used and remains a cornerstone and an effective antihyperglycemic drug. After the casual discovery of its hypoglycemic potential, this compound was introduced for diabetes treatment. However, the long-term side effects reveal that glibenclamide should be replaced by new molecules able to maintain the health of ß-cells, protecting them from hyperstimulation/hyperexcitability, hyperinsulinemia, functional failure and cell death. The aim of this review was to highlight the main mechanism of action of glibenclamide and the influence of its derivatives, such as acylhydrazones, sulfonamides and sulfonylthioureas on ß-cells potassium and calcium channels for insulin secretion as well as the contribution of these new compounds to restore glucose homeostasis. Furthermore, the role of glibenclamide-based novel structures that promise less excitability of ß-cell in a long-term treatment with effectiveness and safety for diabetes therapy was discussed.


Assuntos
Canais de Cálcio/efeitos dos fármacos , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Canais de Potássio/efeitos dos fármacos , Animais , Glibureto/agonistas , Glibureto/química , Homeostase/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Células Secretoras de Insulina/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacologia , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia
9.
Biosci. j. (Online) ; 32(6): 1512-1521, nov./dec. 2016. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-965789

RESUMO

Alternaria brown spot (ABS), caused by the fungus Alternaria alternata pathotype tangerine, is one of the main phytosanitary problems for mandarin growers. About 15 applications per year of harmful fungicides are required for controlling ABS disease in citrus orchards. As chalcones seem to be less toxic to humans and environment than the commercial fungicides in use, this study initially aimed at synthesizing 137 chalcones through aldolic condensations between benzaldehydes and acetophenones. The resulting chalcones were screened for activity against A. alternata through a fungal growth assay that was carried out in 96-cell polypropylene plates, using the same concentration to all studied substances. The four active chalcones underwent conidia germination and mycelial growth, which confirmed the antifungal activity of the compounds. These chalcones were then poured onto Murcott tangor fruit that had been inoculated with conidia of the fungus. All four chalcones reduced the ABS progress to values significantly smaller (P0.05) than that observed for the control. Statistical calculations showed that the best results were afforded by two compounds, bearing a 2,4,5-trimethoxyphenyl group at position 3 of prop-2-enal and a 3-nitro- or 3-hydroxyphenyl group at position 1 of the aldehyde. Such compounds reduced the incidence of the disease in Murcott tangor fruit to values that did not differ statistically from those obtained with a commercial fungicide.


A mancha marron de Alternaria (MMA), causada pelo fungo Alternaria alternata patótipo tangerina, é um dos maiores problemas fitossanitários dos produtores de tangerina. Aproximadamente 15 aplicações de fungicidas de elevada periculosidade, por ano, são necessárias para o controle de MMA em várias plantações de citros. Como as chalconas parecem menos tóxicas para os seres humanos e para o ambiente que os fungicidas comerciais atualmente em uso, este estudo teve como objetivo inicial sintetizar 137 chalconas através da condensação aldólica de benzaldeídos com acetofenonas. As atividades das chalconas resultantes contra A. alternata foram avaliadas através do emprego de teste de crescimento fúngico em placas de polipropileno com 96 cavidades, empregando a mesma concentração para todas as substâncias estudadas. As quatro chalconas mais ativas foram submetidas a testes de germinação de conídios e de crescimento micelial, que confirmaram as atividades antifúngicas dos compostos selecionados. Estes foram então, aplicados em frutos de tangor Murcote que tinham sido inoculados com conídios do fungo. Todas as quatro chalconas reduziram o progresso de MMA a valores significativamente inferiores (P0.05) ao observado para o controle. Cálculos estatísticos mostraram que os melhores resultados foram obtidos para dois compostos, que tinham um grupo 2,4,5-trimetoxifenil na posição 3 do prop-2-enal e um grupo 3-nitro- ou 3-hidroxifenil na posição 1 do aldeído. Tais compostos reduziram a incidência da doença em frutos de tangor Murcote a valores que não diferiam estatisticamente do obtido com um fungicida comercial.


Assuntos
Citrus , Chalconas , Alternaria , Fungicidas Industriais
10.
Anticancer Drugs ; 27(8): 738-47, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27337110

RESUMO

We have previously reported the cytotoxic effects of chalcone A1, derived from 1-naphthaldehyde, in leukemia cell lines. On the basis of these findings, the main aim of this study was to elucidate some of the molecular mechanisms involved in apoptosis induced by chalcone A1 toward K562 and Jurkat cells. In both cell lines, chalcone A1 decreased the mitochondrial membrane potential, increased the expression of Bax proapoptotic protein, and decreased the expression of Bcl-2 antiapoptotic protein (resulting in the inversion of the Bcl-2/Bax ratio), which indicates the involvement of the intrinsic pathway. In addition, chalcone A1 increased the expression of FasR in Jurkat cells, which also indicates the involvement of the extrinsic pathway in this cell line. The results also showed an increased expression of effector caspase-3 and cleaved PARP-1 and a decreased expression of IAP protein survivin, which are consistent with apoptotic cell death. The decreased expression of Ki67 suggests that the mechanism involved in cell death induced by chalcone A1 also involves a decrease in cell proliferation. In ex-vivo experiments, chalcone A1 reduced the cell viability of blast cells collected from eight patients with different types of acute leukemia, confirming the cytotoxicity results found in vitro. The results obtained so far are very promising and further studies need to be carried out so that chalcone A1 can be used as a prototype for the development of new antileukemia agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Leucemia/sangue , Antineoplásicos/química , Fator de Indução de Apoptose/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Células Jurkat , Células K562 , Leucemia/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Survivina , Proteína X Associada a bcl-2/metabolismo
11.
J Cell Biochem ; 117(5): 1199-209, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26447772

RESUMO

To characterize the role and the mechanism of action of (2E)-N'-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (BZD) on incretin secretion, glucose uptake in skeletal muscle and α-glucosidase activity on intestine, targets for glucose homeostasis. It was assayed on glucose tolerance test (GTT) to analyze GLP-1 secretion and the activity of DPP-4 enzyme in vitro. In skeletal muscle, mechanism of action on glucose uptake was carried out by in vitro experiments. The activity of intestinal disaccharidases was performed after in vivo and in vitro experiments. The compound improved the glucose tolerance around 30%, 25%, and 20% at 15, 30, and 60 min, respectively and potentiated the sitagliptin effect, an inhibitor of the enzyme that removes GLP-1, about 50, 45, and 54% at 15, 30, and 60 min, respectively. Additionally, BZD did not modify the activity of DPP-4 enzyme. The acute effect of BZD on glucose uptake is mediated by increasing GLUT4 expression (around 140%) and its translocation to the plasma membrane in soleus muscle. The genomic effect as well as GLUT4 translocation involve the activation of PI-3K and MAPK pathways and require the microtubules integrity to the complete stimulatory effect of this compound on glucose uptake. Beyond, BZD acts in an alternative target to ameliorate glycaemia, intestinal disaccharidases. In a whole, these data point an incretino- and insulinomimetic effect of the compound for glycemic control.


Assuntos
Anisóis/farmacologia , Glicemia/metabolismo , Homeostase/efeitos dos fármacos , Hidrazonas/farmacologia , Incretinas/metabolismo , Insulina/metabolismo , Animais , Dipeptidil Peptidase 4/metabolismo , Dissacaridases/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Glucose/farmacocinética , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes/farmacologia , Immunoblotting , Secreção de Insulina , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos Wistar
12.
Int J Nanomedicine ; 10: 5529-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26366075

RESUMO

Nanoemulsions are drug delivery systems that may increase the penetration of lipophilic compounds through the skin, enhancing their topical effect. Chalcones are compounds of low water solubility that have been described as promising molecules for the treatment of cutaneous leishmaniasis (CL). In this context, the aim of this work was to optimize the development of a nanoemulsion containing a synthetic chalcone for CL treatment using a 2(2) full factorial design. The formulations were prepared by spontaneous emulsification and the experimental design studied the influence of two independent variables (type of surfactant - soybean lecithin or sorbitan monooleate and type of co-surfactants - polysorbate 20 or polysorbate 80) on the physicochemical characteristics of the nanoemulsions, as well as on the skin permeation/retention of the synthetic chalcone in porcine skin. In order to evaluate the stability of the systems, the antileishmanial assay was performed against Leishmania amazonensis 24 hours and 60 days after the preparation of the nanoemulsions. The formulation composed of soybean lecithin and polysorbate 20 presented suitable physicochemical characteristics (droplet size 171.9 nm; polydispersity index 0.14; zeta potential -39.43 mV; pH 5.16; and viscosity 2.00 cP), drug content (91.09%) and the highest retention in dermis (3.03 µg·g(-1)) - the main response of interest - confirmed by confocal microscopy. This formulation also presented better stability of leishmanicidal activity in vitro against L. amazonensis amastigote forms (half maximal inhibitory concentration value 0.32±0.05 µM), which confirmed the potential of the nanoemulsion soybean lecithin and polysorbate 20 for CL treatment.


Assuntos
Antiparasitários/farmacologia , Chalcona/farmacologia , Sistemas de Liberação de Medicamentos , Leishmaniose Cutânea/tratamento farmacológico , Nanoestruturas/química , Administração Cutânea , Antiparasitários/química , Linhagem Celular Tumoral , Chalcona/química , Fenômenos Químicos , Emulsões , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Lecitinas/química , Lecitinas/farmacologia , Tamanho da Partícula , Polissorbatos/química , Polissorbatos/farmacologia , Pele/efeitos dos fármacos , Pele/parasitologia , Solubilidade , Relação Estrutura-Atividade , Tensoativos/química , Tensoativos/farmacologia , Viscosidade
13.
Intervirology ; 57(6): 375-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25359160

RESUMO

OBJECTIVE: To study the anti-herpes simplex virus (HSV) activity of a (1→6)-(1→3)-ß-D-glucan isolated from Agaricus brasiliensis fruiting bodies (FR) as well as its chemically sulfated derivative (FR-S). METHODS: The antiherpetic activity and mechanism of action was studied by viral plaque assay applying different methodological strategies. RESULTS: Although FR presented no in vitro antiherpetic action at 1 mg/ml, FR-S displayed promising anti-HSV-1 and anti-HSV-2 activities in both simultaneous and postinfection treatments, resulting in selectivity indices (CC50/EC50) higher than 393. FR-S had no virucidal effect, but significantly suppressed HSV-1 (EC50 = 0.32 µg/ml) and HSV-2 (EC50 = 0.10 µg/ml) adsorption. FR-S was less effective on adsorption inhibition of mutant virus strains devoid of gC (HSV-1 gC⁻39 and HSV-2 gCneg1), indicating a possible interaction with this glycoprotein. The reduction of viral adsorption upon cell pretreatment with FR-S also suggests its interaction with cellular components. FR-S inhibited HSV-1 (EC50 = 8.39 µg/ml) and HSV-2 (EC50 = 2.86 µg/ml) penetration more efficiently than heparin. FR-S reduced HSV-1 and HSV-2 cell-to-cell spread. A synergic effect between FR-S and acyclovir was also detected. CONCLUSIONS: FR-S displays an interesting mechanism of antiviral action and represents a promising candidate for the treatment and/or prevention of herpetic infections, to be used as a single therapeutic agent or in combination with acyclovir.


Assuntos
Agaricus/química , Antivirais/química , Antivirais/farmacologia , Carpóforos/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Polissacarídeos/farmacologia , beta-Glucanas/farmacologia , Aciclovir/farmacologia , Animais , Brasil , Chlorocebus aethiops , Sinergismo Farmacológico , Polissacarídeos/química , Células Vero , Ensaio de Placa Viral , beta-Glucanas/química , beta-Glucanas/isolamento & purificação
14.
Eur J Med Chem ; 86: 491-501, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25203779

RESUMO

Glibenclamide is widely used in the management of non-insulin dependent diabetes mellitus, but numerous risks limit its use in therapy. In the search for novel structures that are safer and more efficient than glibenclamide, we obtained new chemical analogs based on bioisosterism, through the treatment of benzenesulfonamide derivatives with isothiocyanates and isocyanates, affording (thio)ureas with good yield. We also verified the hypoglycemic activity, through an in vivo approach. Most of these synthesized compounds improved glucose tolerance, and the mechanism of action of the best compound (7) suggests that its effect is mediated by insulin secretion, while its hypoglycemic action is triggered by glucose uptake involving GLUT4 expression and translocation through PI-3K and PKA activity and active de novo protein synthesis in skeletal muscle. Taking all these factors together, sulfonylthiourea 7 acts as an insulin secretagogue and insulinomimetic agent on glucose homeostasis, and does not exhibit toxicity in acute treatment.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Animais , Diabetes Mellitus Experimental/patologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina/fisiologia , Secreção de Insulina , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/uso terapêutico
15.
Drug Des Devel Ther ; 8: 609-19, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24920885

RESUMO

A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Chalconas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Quinoxalinas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/síntese química , Antineoplásicos/química , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
16.
Toxicol In Vitro ; 28(5): 769-77, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24583196

RESUMO

Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cálcio/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Citocromos c/metabolismo , Estresse do Retículo Endoplasmático , Expressão Gênica , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Camundongos , Células NIH 3T3 , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Células Vero , Receptor fas/genética , Receptor fas/metabolismo
17.
PLoS One ; 9(1): e84531, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24400098

RESUMO

The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(Sc) aggregates and catalyzes PrP(C) misfolding into new PrP(Sc) molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrP(Sc) (ScN2a) for their ability to inhibit PK-resistant PrP (PrP(Res)) accumulation. From ∼200 compounds, 47 were effective in decreasing the accumulation of PrP(Res) in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrP(Res) from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP(109-149)). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrP(Res) in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are attractive candidates for prion disease therapy.


Assuntos
Compostos Heterocíclicos/farmacologia , Príons/efeitos dos fármacos , Animais , Linhagem Celular , Simulação por Computador , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Príons/química , Conformação Proteica
18.
Chem Res Toxicol ; 26(12): 1904-16, 2013 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-24304350

RESUMO

Cyclic imides are known for their antitumor activity, especially the naphthalimide derivatives, such as Mitonafide and Amonafide. Recently, we have demonstrated the cytotoxic effect of a series of naphthalimide derivatives against B16F10 melanoma cells. On the basis of this fact, we have developed a study starting from the synthesis of different cyclic imides and the evaluation of their cytotoxic properties on human acute leukemia cells (K562 and Jurkat). Initially, a screening test was conducted to select the compound with the best cytotoxic effect, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After this selection, structural modifications were performed in the most active compound to obtain five more derivatives. All compounds presented a good cytotoxic effect. The results of cell cycle analysis, fluorescence microscopy, and Annexin V-FITC assay confirmed that the cells observed in the sub-G0/G1 phase were undergoing apoptosis. From this set of results, cyclic imides 8, 10, and 12 were selected for the evaluation of the mechanisms involved in the apoptotic process. The results demonstrate the involvement of the intrinsic pathway of apoptosis, evidenced by the reduction in mitochondrial potential, an increase in the level of AIF protein expression, a decreased level of expression of anti-apoptotic Bcl-2 protein, and an increased level of expression of pro-apoptotic protein Bax in both K562 and Jurkat cells treated with cyclic imides (8, 10, and 12). Furthermore, cyclic imides 8 and 10 caused an increase in the level of Fas expression in Jurkat cells, indicating the additional involvement of the extrinsic apoptosis pathway. The compounds (8, 10, and 12) also caused a decreased level of expression of anti-apoptotic protein survivin. The biological effects observed with these cyclic imide derivatives in this study suggest promising applications against acute leukemia.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia/patologia , Maleimidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Jurkat , Células K562 , Maleimidas/síntese química , Maleimidas/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Exp Parasitol ; 135(4): 661-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24140596

RESUMO

Meloidogyne exigua is a parasitic nematode of plants that causes great losses to coffee farmers. In an effort to develop parasitic controls, 154 chalcones were synthesized and screened for activity against this nematode. The best results were obtained with (2E)-1-(4'-nitrophenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (6) with a 50% lethal concentration (LC50) of 171 µg/ml against M. exigua second-stage juveniles, in comparison to the commercially-available nematicide carbofuran which had an LC50 of 260 µg/ml under the same conditions. When coffee plants were used, 6 reduced the nematode population to ~50% of that observed in control plants. To investigate the mechanism of action of 6, an in silico study was carried out, which indicated that 6 may act against M. exigua through inhibition of a putative caffeic acid 3-O-methyltransferase homodimer, the amino acid sequence of which was determined by examining the genome of Meloidogyne incognita.


Assuntos
Benzaldeídos/química , Chalconas/farmacologia , Coffea/parasitologia , Metiltransferases/antagonistas & inibidores , Tylenchoidea/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Chalconas/química , Chalconas/isolamento & purificação , Dose Letal Mediana , Ligantes , Medicago sativa/enzimologia , Metiltransferases/química , Dados de Sequência Molecular , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Tylenchoidea/enzimologia
20.
PLoS One ; 8(10): e77081, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24155919

RESUMO

Protein tyrosine phosphatase B (PtpB) is one of the virulence factors secreted into the host cell by Mycobacterium tuberculosis. PtpB attenuates host immune defenses by interfering with signal transduction pathways in macrophages and, therefore, it is considered a promising target for the development of novel anti-tuberculosis drugs. Here we report the discovery of natural compound inhibitors of PtpB among an in house library of more than 800 natural substances by means of a multidisciplinary approach, mixing in silico screening with enzymatic and kinetics studies and MS assays. Six natural compounds proved to inhibit PtpB at low micromolar concentrations (< 30 µM) with Kuwanol E being the most potent with K i = 1.6 ± 0.1 µM. To the best of our knowledge, Kuwanol E is the most potent natural compound PtpB inhibitor reported so far, as well as it is the first non-peptidic PtpB inhibitor discovered from natural sources. Compounds herein identified may inspire the design of novel specific PtpB inhibitors.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Sequência de Aminoácidos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Produtos Biológicos/química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mapeamento de Peptídeos , Ligação Proteica/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Tirosina Fosfatases/química , Proteólise
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