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1.
J Med Chem ; 64(4): 1904-1929, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626870

RESUMO

The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.

2.
Eur J Pharm Sci ; 159: 105731, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33493668

RESUMO

The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.

3.
Neurobiol Stress ; 13: 100226, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32478146

RESUMO

Post-traumatic stress disorder (PTSD) is a mental health condition that is triggered by a stressful event, with symptoms including exaggerated startle response, intrusive traumatic memories and nightmares. The single prolonged stress (SPS) is a multimodal stress protocol that comprises a sequential exposure to physical restraint, forced swimming, predator scent and ether anesthesia. This procedure generates behavioral and neurobiological alterations that resemble clinical findings of PTSD, and thus it is commonly used to model the disease in rodents. Here, we applied c-fos mapping to produce a comprehensive view of stress-activated brain regions in mice exposed to SPS alone or to SPS after oral pretreatment with the serotonin-noradrenaline receptor dual modulator ACH-000029 or the α1-adrenergic blocker prazosin. The SPS protocol evoked c-fos expression in several brain regions that control the stress-anxiety response, including the central and medial amygdala, the bed nucleus of the stria terminalis, the pallidum, the paraventricular hypothalamus, the intermediodorsal, paraventricular and central medial thalamic nuclei, the periaqueductal gray, the lateral habenula and the cuneiform nucleus. These effects were partially blocked by pretreatment with prazosin but completely prevented by ACH-000029. Collectively, these findings contribute to the brain-wide characterization of neural circuits involved in PTSD-related stress responses. Furthermore, the identification of brain areas regulated by ACH-000029 and prazosin revealed regions in which SPS-induced activation may depend on the combined or isolated action of the noradrenergic and serotonergic systems. Finally, the dual regulation of serotonin and α1 receptors by ACH-000029 might represent a potential pharmacotherapy that can be applied in the peri-trauma or early post-trauma period to mitigate the development of symptoms in PTSD patients.

4.
Neuropharmacology ; 164: 107912, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31843397

RESUMO

Post-traumatic stress disorder (PTSD) is a severe chronic mental illness that develops in individuals exposed to life-threatening trauma and is characterized by hyperarousal, flashbacks and nightmares. The serotonergic (5-HT) and noradrenergic (NE) systems are deeply involved in the pathogenesis of PTSD. We have previously reported a novel anxiolytic compound, ACH-000029, that modulates 5-HT and α1-adrenergic receptors and induces acute anxiolytic-like effects in rodents. Here, we investigated the potential of ACH-000029 to prevent anxiety-like behavior in the single prolonged stress (SPS) PTSD model. Mice were subjected to the SPS procedure, followed by a 7-day treatment with ACH-000029 and, for comparison, with the α1-adrenergic antagonist prazosin. Animals were behaviorally assessed using social interaction, elevated plus maze and open field tests. Interestingly, treatment with ACH-000029 but not with prazosin ameliorated the SPS-induced sociability impairment and anxiety-like behavior. The brain-wide c-fos mapping, used as a surrogate for brain activity, indicated the brain structures that were altered by SPS and putatively involved in the anxiolytic-like effect of ACH-000029. The SPS protocol produced long-lasting impairment of regions involved in stress-anxiety response, such as the amygdala, prefrontal cortex, globus pallidus and superior colliculus. ACH-000029 treatment reversed the SPS-induced c-fos changes in the globus pallidus, lateral septum and entorhinal cortex and exclusively modulated c-fos levels in subregions from the retrosplenial cortex, cerebellum, superior colliculus and ventromedial hypothalamus. These results support the hypothesis that the dual regulation of 5-HT and α1-adrenergic receptors is required to alleviate PTSD symptoms and suggest a possible role of ACH-000029 as a PTSD treatment.

5.
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.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31330215

RESUMO

Anxiety disorders are serious and common mental diseases, yet there is still a need for the development of more effective anxiolytics with better safety profiles than benzodiazepines and serotonin reuptake inhibitors. The serotonergic and noradrenergic systems have reciprocal interactions and are intricately related to the pathogenesis of anxiety. In this study, the anxiolytic-like effect of the novel compound ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, is reported. This compound acts at selected serotonergic (5-HT1A and 5-HT1D partial agonism and 5-HT2A antagonism) and α-adrenergic (α-1A, 1B and 1D antagonism) receptors, with good selectivity over other G-protein-coupled receptors. ACH-000029 exhibited high blood-brain barrier permeation and acute anxiolytic effects in the marble burying (MB) and light-dark box (LDB) models of anxiety over the dose ranges of 8-32 mg/kg i.p. and 16-30 mg/kg p.o. The anxiolytic activity was comparable to that observed for serotonin reuptake inhibitors (paroxetine and fluoxetine) and benzodiazepines (alprazolam, diazepam and clobazam). The analysis of the whole-brain c-fos expression following oral dosing showed that ACH-000029 regulated regions highly associated with the processing of environmental stimuli and anxiety behavior, such as the amygdala, paraventricular nucleus of the thalamus, retrosplenial dorsal, pallidum, bed nuclei of the stria terminalis, and locus ceruleus. No safety concerns were identified for ACH-000029 in the functional observational battery up to 50 mg/kg i.p. and in the nonprecipitated withdrawal test up to 30 mg/kg p.o. twice daily for 20 days. This work supports the further development of ACH-000029 as a drug candidate for the treatment of anxiety disorders. The analysis of the in vitro pharmacology and brain regions regulated by this compound may also lead to the exploration of other indications within the psychiatry field.


Assuntos
Adrenérgicos/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Serotoninérgicos/farmacologia , Adrenérgicos/uso terapêutico , Animais , Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Serotoninérgicos/uso terapêutico
7.
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
8.
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
9.
PLoS One ; 13(8): e0202568, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30114296

RESUMO

New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis. Six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratorial strain. The three compounds (N9, N15 and N23) with the lowest MIC values were further tested against clinical isolates and laboratory strains with mutations in katG or inhA genes. From these data, N9 was selected as the lead compound for further investigation. Importantly, this chalcone displayed a synergistic effect when combined with moxifloxacin. Noteworthy, the anti-tubercular effects of N9 did not rely on inhibition of mycolic acids synthesis, circumventing important mechanisms of resistance. Interactions with cytochrome P450 isoforms and toxic effects were assessed in silico and in vitro. The chalcone N9 was not predicted to elicit any mutagenic, genotoxic, irritant, or reproductive effects, according to in silico analysis. Additionally, N9 did not cause mutagenicity or genotoxicity, as revealed by Salmonella/microsome and alkaline comet assays, respectively. Moreover, N9 did not inhibit the cytochrome P450 isoforms CYP3A4/5, CYP2C9, and CYP2C19. N9 can be considered a potential lead molecule for development of a new anti-tubercular therapeutic agent.


Assuntos
Antituberculosos/farmacologia , Chalconas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Proteínas de Bactérias/genética , Catalase/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Sistema Enzimático do Citocromo P-450/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/patogenicidade , Ácidos Micólicos/antagonistas & inibidores , Oxirredutases/genética , Quinoxalinas/farmacologia , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/patologia
10.
J Cell Biochem ; 119(6): 4408-4419, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29130561

RESUMO

The aim of the present study was to investigate the mechanism of action of a sulfonamide derivative on glucose uptake in adipose tissue, as well as to characterize the effects of this compound on intestinal disaccharidases and advanced glycation end-products (AGEs) formation. Camphoryl-benzene sulfonamide (CS) was able to stimulate glucose uptake in isolated adipocytes, adipose tissue, and in soleus muscle. The stimulatory effect of the compound (10 µM) on glucose uptake on adipose tissue was blocked by diazoxide, wortmannin, U73122, colchicine, and N-ethylmaleimide. On the other hand, the effects of CS were not blocked by glibenclamide, an inhibitor of the K+ -ATP channel, or even by the inhibitor of protein p38 MAPK, SB 203580. In vivo, this compound reduced intestinal disaccharidase activity, while, in vitro, CS reduced the formation of AGEs at 7, 14, and 28 days of incubation. The stimulatory effect of CS on glucose uptake requires the activation of the K+ -ATP channel, translocation, and fusion of GLUT4 vesicles to the plasma membrane on adipocytes for glucose homeostasis. In addition, the inhibition of disaccharidase activity contributes to the glucose homeostasis in a short-term as well as the remarkable reduction in AGE formation indicates that the CS may prevent of complications of late diabetes.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Membrana Celular/metabolismo , Glucose/metabolismo , Sulfonamidas/farmacologia , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Membrana Celular/patologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Dissacarídeos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Ratos , Ratos Wistar
11.
Eur J Med Chem ; 144: 277-288, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29275228

RESUMO

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (Ki = 1.6 ± 0.1 µM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed Ki values of 0.39 ± 0.27 and 0.20 ± 0.01 µM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB.


Assuntos
Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Morus/química , Mycobacterium tuberculosis/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Linhagem Celular , Reação de Cicloadição , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade
12.
Sci Rep ; 7(1): 15850, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29158524

RESUMO

The present study aimed to characterize the effects of quinoxaline-derived chalcones, designed on the basis of the selective PI3Kγ inhibitor AS605240, in oral cancer cells. Three lead compounds, namely N9, N17 and N23, were selected from a series of 20 quinoxaline-derived chalcones, based on an initial screening using human and rat squamous cell carcinoma lineages, representing compounds with at least one methoxy radical at the A-ring. The selected chalcones, mainly N9 and N17, displayed marked antiproliferative effects, via apoptosis and autophagy induction, with an increase of sub-G1 population and Akt inhibition. The three chalcones displayed marked in vitro antitumor effects in different protocols with standard chemotherapy drugs, with acceptable toxicity on normal cells. There was no growth retrieval, after exposure to chalcone N9 alone, in a long-term assay to determine the cumulative population doubling (CPD) of human oral cancer cells. A PCR array evaluating 168 genes related to cancer and inflammation, demonstrated striking actions for N9, which altered the expression of 74 genes. Altogether, our results point out quinoxalinic chalcones, mainly N9, as potential strategies for oral cancer treatment.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Proteínas de Neoplasias/genética , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Quinoxalinas/química , Ratos , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia
13.
Sci Rep ; 7(1): 7501, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28790404

RESUMO

The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.


Assuntos
Antineoplásicos/química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pteridinas/química , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Genoma Humano , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pteridinas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Vírus Vaccinia/genética , Vírus Vaccinia/metabolismo
14.
Anticancer Drugs ; 28(9): 977-988, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28746057

RESUMO

Metastasis is the main cause of cancer-related death and requires the development of effective treatments with reduced toxicity and effective anticancer activity. Gallic acid derivatives have shown significant biological properties including antitumoral activity as shown in a previous study with octyl gallate (G8) in vitro. Thus, the aim of this work was to evaluate the antimetastatic effect of free and solid lipid nanoparticle-loaded G8 in mice in a lung metastasis model. Animals inoculated with melanoma cells presented metastasis in lungs, which was significantly inhibited by treatment with G8 and solid lipid nanoparticle-loaded G8, named G8-NVM. However, G8-treated mice showed an increase in several toxicological parameters, which were almost completely circumvented by G8-NVM treatment. This study supports the need for pharmacological studies on new potential medicinal plants to treat cancer and can provide new perspectives on using nanotechnology to improve biological activities while decreasing the chemotherapy toxicological effects of anticancer drugs.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ácido Gálico/análogos & derivados , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Chlorocebus aethiops , Feminino , Ácido Gálico/administração & dosagem , Ácido Gálico/efeitos adversos , Ácido Gálico/química , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Nanopartículas/química , Metástase Neoplásica , Espécies Reativas de Oxigênio/metabolismo , Células Vero
15.
Biochimie ; 140: 48-57, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28610775

RESUMO

Chalcones are natural compounds described in the literature by its several properties including cytotoxic activity against several tumor types. Considering that the search for new chemotherapeutic agents is still necessary, the aim of this study was to investigate the cytotoxic mechanisms involved in cell death induced by a synthetic chalcone (A23) on different tumor cells. Chalcone A23 reduced the cell viability of twelve tumor cell lines in a concentration and time dependent manner and it was more cytotoxic against acute leukemia cells. Interestingly, the compound was non cytotoxic to normal cells and non-hemolytic to normal red blood cells. Chalcone A23 decreased the expression of cell proliferation marker KI-67 and blocked the G2/M phase in both K562 and Jurkat cell lines. Cells treated with A23 showed morphological features suggestive of apoptosis, the "latter pattern" in agarose gel, the externalization of phosphatidylserine and caspase-3 and PARP cleavage. Chalcone A23 significantly reduced the mitochondrial membrane potential, decreased the expression of anti-apoptotic proteins Bcl-2 and survivin and increased the expression of pro-apoptotic protein Bax, confirming the involvement of the intrinsic pathway. The increased mitochondrial permeability resulted in the release of AIF, cytochrome c and endonuclease G from the mitochondria to the cytosol. In addition, chalcone A23 increased the expression of FasR and induced Bid cleavage, showing the involvement of the extrinsic pathway. Finally, chalcone A23 seems to have a synergic effect with the chemotherapy drugs cytarabine and vincristine. These results suggest that A23 is an interesting compound with strong and selective anti-tumor activity.


Assuntos
Apoptose/efeitos dos fármacos , Chalconas , Citotoxinas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Proteínas de Neoplasias/biossíntese , Células A549 , Animais , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HL-60 , Células HeLa , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Células Jurkat , Masculino , Camundongos , Células NIH 3T3 , Proteínas de Neoplasias/genética , Células U937
16.
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
17.
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
18.
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
19.
Chem Biol Interact ; 252: 74-81, 2016 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-27012433

RESUMO

Glioblastoma multiforme is the main and most frequent tumor in adults' central nervous system. With a survival average of 5% two years after diagnosis, this type of cancer is a main health problem. Substances like the chalcones have been tested in order to develop new treatments. Here, we studied the effects of three synthetic chalcones (A23, C31 and J11) on A172 and surgery obtained-glioma cells. All chalcones showed a decrease in cell viability, mainly C31. An increase in apoptosis levels with no further increase of necrosis was observed. This augmentation may be linked to the high oxidative effect found, caused by the increased presence of reactive oxygen species and nitric oxide production. Cell cycle distribution showed an arrest at G0/G1 and S phases, suggesting that C31 interferes in cell cycle control. Our results shall aid in directing future research with this substance and its antitumor effect.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Chalconas/farmacologia , Glioblastoma/tratamento farmacológico , Antineoplásicos/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
20.
Curr Pharm Des ; 22(12): 1561-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26759082

RESUMO

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which primarily affects the respiratory tract. Combinations of drugs are used for therapeutic synergism and to prevent the emergence of drug resistant strains, but even first- or secondchoice drugs present some disadvantages, such as significant side effects and the need for long duration of treatments. Thus, new strategies for TB control and treatment are highly demanded. In this context, protein tyrosine phosphatases (PtpA and PtpB) are secreted by Mtb within the host macrophage and they have been shown to contribute to Mtb pathogenicity. The understanding of the role of these PTPs has led to interesting anti-TB drugs discovery. Here, we review the current knowledge on these two proteins as targets for novel anti-TB therapies, with particular emphasis on their mechanism of action and current advancements in developing small molecule inhibitors from natural sources.


Assuntos
Antituberculosos/farmacologia , Produtos Biológicos/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Tuberculose/tratamento farmacológico , Antituberculosos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Relação Estrutura-Atividade , Tuberculose/microbiologia
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