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1.
Eur J Med Chem ; 210: 113073, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33310287

RESUMO

Isochromans are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Medicinal chemistry investigators have synthesized drug-like isochroman candidates with multiple medicinal features including central nervous system (CNS), antioxidant, antimicrobial, antihypertensive, antitumor and anti-inflammatory agents. Simultaneously, SAR (Structure-Activity Relationship) analysis has drawn attentions among medicinal chemists, along with a great deal of derivatives have been derived for potential targets. In this article, we thoroughly summarize the biological activities and part of typical SAR for isochroman derivatives reported on existing literatures and patents, wishing to provide an overall retrospect and prospect on the isochroman analogues.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Cromanos/farmacologia , Animais , Anti-Infecciosos/química , Anti-Inflamatórios/química , Anti-Hipertensivos/química , Antineoplásicos/química , Antioxidantes/química , Cromanos/química , Humanos , Estrutura Molecular
2.
Food Chem ; 345: 128468, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33341300

RESUMO

Antioxidant interactions of γ-terpinene with α-tocopherol mimic 2,2,5,7,8-pentamethyl-6-chromanol (PMHC) and caffeic acid phenethyl ester (CAPE), used as models, respectively, of mono- and poly-phenols were demonstrated by differential oximetry during the inhibited autoxidation of model substrates: stripped sunflower oil, squalene, and styrene. With all substrates, γ-terpinene acts synergistically regenerating the chain-breaking antioxidants PMHC and CAPE from their radicals, via the formation of hydroperoxyl radicals. The inhibition duration for mixtures PMHC/γ-terpinene and CAPE/γ-terpinene increased with γ-terpinene concentration, while rate constants for radical-trapping were unchanged by γ-terpinene, being 3.1 × 106 and 4.8 × 105 M-1s-1 for PMHC and CAPE in chlorobenzene (30 °C). Using 3,5-di-tert-butylcatechol and 3,5-di-tert-butyl-1,2-bezoquinone we demonstrate that γ-terpinene can reduce quinones to catechols enabling their antioxidant activity. The different synergy mechanism of γ-terpinene with mono- and poly-phenolic antioxidants is discussed and its relevance is proven in homogenous lipids using natural α-tocopherol and hydroxytyrosol as antioxidants, calling for further studies in heterogenous food products.


Assuntos
Monoterpenos Cicloexânicos/química , Monoterpenos Cicloexânicos/farmacologia , Peróxidos/química , Fenóis/química , Fenóis/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Sinergismo Farmacológico , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia
3.
J Pharmacol Sci ; 143(3): 226-233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446726

RESUMO

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Cromanos/farmacologia , Cromanos/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Fator de Necrose Tumoral alfa/metabolismo
4.
Mar Drugs ; 18(2)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019233

RESUMO

Side-chain derivatives of eurotiumide A, a dihydroisochroman-type natural product, have been synthesized and their antimicrobial activities described. Sixteen derivatives were synthesized from a key intermediate of the total synthesis of eurotiumide A, and their antimicrobial activities against two Gram-positive bacteria, methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), and a Gram-negative bacterium, Porphyromonas gingivalis, were evaluated. The results showed that derivatives having an iodine atom on their aromatic ring instead of the prenyl moiety displayed better antimicrobial activity than eurotiumide A against MSSA and P. gingivalis. Moreover, we discovered that a derivative with an isopentyl side chain, which is a hydrogenated product of eurotiumide A, is the strongest antimicrobial agent against all three strains, including MRSA.


Assuntos
Antibacterianos/farmacologia , Cromanos/farmacologia , Porphyromonas gingivalis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Cromanos/síntese química , Cromanos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165727, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070771

RESUMO

Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature. Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid ß-oxidation. However, the therapeutic potential of this mixed PPAR (α, δ/ß, γ) agonist is severely hampered by hepatotoxicity, which is possibly caused by activation of PPARγ. Here, we aimed to investigate the effects of the PPARα-specific fibrate clofibrate in mitochondrial CI-deficient (Ndufs4-/-) mice. Clofibrate increased lifespan and motor function of Ndufs4-/- mice, while only marginal hepatotoxic effects were observed. Due to the complex clinical and cellular phenotype of CI-deficiency, we also aimed to investigate the therapeutic potential of clofibrate combined with the redox modulator KH176. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4-/- mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases.


Assuntos
Cromanos/farmacologia , Clofibrato/farmacologia , Complexo I de Transporte de Elétrons/deficiência , Longevidade/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Bezafibrato/farmacologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Ácidos Graxos/metabolismo , Humanos , Doença de Leigh/tratamento farmacológico , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Atividade Motora/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética
6.
Molecules ; 25(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963634

RESUMO

Prostate cancer is the second most commonly diagnosed cancer in men, and metastatic prostate cancer is currently incurable. Prostate cancer frequently becomes resistant to standard of care treatments, and the administration of chemotherapeutic drugs is often accompanied by toxic side effects. Combination therapy is one tool that can be used to combat therapeutic resistance and drug toxicity. Vitamin E (VE) compounds and analogs have been proposed as potential non-toxic chemotherapeutics. Here we modeled combination therapy using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize mixture compositions, to determine whether combinations of three chemotherapeutic agents: γ-tocotrienol (γ-T3), α-tocopherol ether acetate (α-TEA), and docetaxel (DOC), would prove more effective than docetaxel alone in the treatment of human prostate cancer cells. Response surfaces were generated for cell viability, and the optimal treatment combination for reducing cell viability was calculated. We found that a combination of 20 µM γ-T3, 30 µM α-TEA, and 25 nm DOC was most effective in the treatment of PC-3 cells. We also found that the combination of γ-T3 and α-TEA with DOC decreased the amount of DOC required to reduce cell viability in PC-3 cells and ameliorated therapeutic resistance in DOC-resistant PC-3 cells.


Assuntos
Antineoplásicos/farmacologia , Cromanos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Vitamina E/análogos & derivados , alfa-Tocoferol/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Éter , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Vitamina E/farmacologia
7.
Mol Divers ; 24(1): 81-91, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30830596

RESUMO

An efficient procedure for the synthesis of benzochromene derivatives employing 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone (euparin), aldehydes, alkyl bromides, dialkyl acetylenedicarboxylate and triphenylphosphine in the presence of KF/CP NPs as a heterogeneous base nano-catalyst in water at 80 °C is investigated. Also, the antioxidant activity of some synthesized compounds was studied. The workup of mixture of reaction is simple, and the products can be separated easily by filtration. KF/CP NPs showed a good improvement in the yield of the product and displayed significant reusable activity.


Assuntos
Antioxidantes/síntese química , Técnicas de Química Sintética , Cromanos/síntese química , Química Verde , Nanopartículas , Zeolitas/química , Antioxidantes/química , Antioxidantes/farmacologia , Catálise , Cromanos/química , Cromanos/farmacologia , Ferro/química
8.
Oxid Med Cell Longev ; 2019: 4957878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687081

RESUMO

Bovine herpesvirus type 1 (BoHV-1) is a significant cofactor for bovine respiratory disease complex (BRDC), the most important inflammatory disease in cattle. BoHV-1 infection in cell cultures induces overproduction of pathogenic reactive oxygen species (ROS) and the depletion of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a master transcriptional factor regulating a panel of antioxidant and cellular defense genes in response to oxidative stress. In this study, we reported that the virus productive infection in MDBK cells at the later stage significantly decreased the expression levels of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) proteins, the canonical downstream targets regulated by Nrf2, inhibited Nrf2 acetylation, reduced the accumulation of Nrf2 proteins in the nucleus, and relocalized nuclear Nrf2 proteins to form dot-like staining patterns in confocal microscope assay. The differential expression of Kelch-like ECH associated protein 1 (KEAP1) and DJ-1 proteins as well as the decreased association between KEAP1 and DJ-1 promoted Nrf2 degradation through the ubiquitin proteasome pathway. These data indicated that the BoHV-1 infection may significantly suppress the Nrf2 signaling pathway. Moreover, we found that there was an association between Nrf2 and LaminA/C, H3K9ac, and H3K18ac, and the binding ratios were altered following the virus infection. Taken together, for the first time, we provided evidence showing that BoHV-1 infection inhibited the Nrf2 signaling pathway by complicated mechanisms including promoting Nrf2 degradation, relocalization of nuclear Nrf2, and inhibition of Nrf2 acetylation.


Assuntos
Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Herpesvirus Bovino 1/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Acetilação , Animais , Bovinos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cromanos/farmacologia , Herpesvirus Bovino 1/efeitos dos fármacos , Laminas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/metabolismo
9.
Minerva Ginecol ; 71(5): 353-358, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31698889

RESUMO

BACKGROUND: There is a growing interest on women' sexual function improvement provided by topical vulvar application of Visnadine, a natural extractive substance with putative vasodilatory properties. Aims of this study were to evaluate: 1) the vasokinetic activity of a Visnadine Emulgel on mucosal genitalia of 15 healthy postmenopausal women clinically and by instrumental non-invasive analysis; 2) the treatment efficacy by volunteers' judgment regarding to subjective comfort, pleasant warmth, lubrication grade, pinching and burning vulvar sensations. METHODS: Fifteen informed healthy female volunteers with menopause were enrolled in the study, with a single blind controlled study versus placebo corresponding to one single application of the emulgel product (active or placebo) on external genitalia. RESULTS: Visnadine Emulgel single application determined a significant increase of vulvar hyperemia, evaluated both clinically and instrumentally, accompanied by a significant increase of local turgor versus placebo. The volunteers reported a pleasant comfort sensation. CONCLUSIONS: The topical use of Visnadine on female external genitalia may increase regional vascularization affecting turgidity and sensorial threshold of the area of application.


Assuntos
Cromanos/administração & dosagem , Pós-Menopausa , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vulva/efeitos dos fármacos , Administração Tópica , Idoso , Cromanos/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Método Simples-Cego , Resultado do Tratamento , Vulva/irrigação sanguínea
10.
Immunopharmacol Immunotoxicol ; 41(6): 599-606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691624

RESUMO

Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model.Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model.Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model.Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Cromanos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Imunoterapia , Células Supressoras Mieloides/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Camundongos , Células Supressoras Mieloides/patologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Nutrients ; 11(11)2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31744219

RESUMO

Acute myeloid leukemia (AML) is a blood cancer characterized by the formation of faulty defective myelogenous cells with morphological heterogeneity and cytogenic aberrations leading to a loss of their function. In an attempt to find an effective and safe AML treatment, vitamin E derivatives, including tocopherols were considered as potential anti-tumor compounds. Recently, other isoforms of vitamin E, namely tocotrienols have been proposed as potential potent anti-cancerous agents, displaying promising therapeutic effects in different cancer types. In this study we evaluated the anti-cancerous effects of γ-tocotrienol, on AML cell lines in vitro. For this purpose, AML cell lines incubated with γ-tocotrienol were examined for their viability, cell cycle status, apoptotic cell death, DNA fragmentation, production of reactive oxygen species and expression of proapoptotic proteins. Our results showed that γ-tocotrienol exhibits time and dose-dependent anti-proliferative, pro-apoptotic and antioxidant effects on U937 and KG-1 cell lines, through the upregulation of proteins involved in the intrinsic apoptotic pathway.


Assuntos
Antineoplásicos/farmacologia , Cromanos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Vitamina E/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Vitamina E/farmacologia
12.
Cells ; 8(11)2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694317

RESUMO

The three subtypes (α, ß, and γ) of the retinoic acid receptor (RAR) are ligand-dependent transcription factors that mediate retinoic acid signaling by forming heterodimers with the retinoid X receptor (RXR). Heterodimers are functional units that bind ligands (retinoids), transcriptional co-regulators and DNA, to regulate gene networks controlling cell growth, differentiation, and death. Using biochemical, crystallographic, and cellular approaches, we have set out to explore the spectrum of possibilities to regulate RXR-RAR heterodimer-dependent transcription through various pharmacological classes of RAR- and RXR- specific ligands, alone or in combination. We reveal the molecular details by which these compounds direct specificity and functionality of RXR-RAR heterodimers. Among these ligands, we have reevaluated and improved the molecular and structural definition of compounds CD2665, Ro41-5253, LE135, or LG100754, highlighting novel functional features of these molecules. Our analysis reveals a model of RXR-RAR heterodimer action in which each subunit retains its intrinsic properties in terms of ligand and co-regulator binding. However, their interplay upon the combined action of RAR- and RXR-ligands allows for the fine tuning of heterodimer activity. It also stresses the importance of accurate ligand characterization to use synthetic selective retinoids appropriately and avoid data misinterpretations.


Assuntos
Receptores do Ácido Retinoico/metabolismo , Receptores X Retinoide/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Benzoatos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Cromanos/farmacologia , Dibenzazepinas/farmacologia , Dimerização , Humanos , Ligantes , Células MCF-7 , Subunidades Proteicas/metabolismo , Retinoides/farmacologia , Tetra-Hidronaftalenos/farmacologia
13.
Future Med Chem ; 11(20): 2687-2699, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31596141

RESUMO

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/química , Cromanos/química , Desenho de Fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Cromanos/síntese química , Cromanos/farmacologia , Humanos , Modelos Moleculares
14.
J Physiol Pharmacol ; 70(3)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31566191

RESUMO

We hypothesized that the repolarization phase of action potentials (APs) in mammals with large body mass and high cardiac output could not be reliably controlled by only one of the delayed rectifier potassium IK current components. To test this hypothesis experimentally, we performed a comparative study of the response of AP phases to the rapid IKr channels blocker E-4031 and slow IKs blocker chromanol 293B in APs spontaneously generated in strips of sinoauricular (SA) tissue from mouse, guinea pig, and pig hearts. Application of a slow channels blocker chromanol 293B caused a decrease of Aps generation frequency in SA area strips from mouse, guinea-pig and pig by 5.3, 16, and 18% compared to the control. Treatment with the IKr blocker E-4031 caused a significant reduction of APs generation frequency in the mouse, guinea pig, and pig SA strips by 24, 26, and 36%, respectively, compared to the control values. These results suggest that the rapid IKr current is the key component responsible for AP generation in sinoauricular node cells of the pig heart.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Potássio/metabolismo , Potássio/metabolismo , Nó Sinoatrial/fisiologia , Animais , Cromanos/farmacologia , Cobaias , Masculino , Camundongos , Bloqueadores dos Canais de Potássio/farmacologia , Nó Sinoatrial/metabolismo , Sulfonamidas/farmacologia , Suínos
15.
Bioorg Med Chem Lett ; 29(19): 126636, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31474483

RESUMO

Sixteen ß-keto sulfide derivatives of carvacrol (4-19) incorporating phenyl or N, O and S heterocyclic moieties were synthesized in three steps. The relationships between heterocyclic structure and cupric, Cu(II), ion reducing antioxidant capacity (CUPRAC) were examined. Nine of the compounds (8-9 and 13-19) showed better CUPRAC activity than trolox at neutral pH, with trolox equivalent antioxidant capacity (TEAC) coefficients ranging between 1.20 and 1.75. Two derivatives (11-12) showed comparable reducing capacity to trolox, with TEAC values of 0.95 for 11 and 1.02 for 12. Compounds 8-9 and 11-19 were more effective at reducing the Cu(II) ion than ascorbic acid and the parent compound, carvacrol. The most effective antioxidants were those containing an oxadiazole, thiadiazole or triazole moiety. In particular, the methyl thiadiazole derivative (15) had the highest Cu(II) ion reducing capacity, with a TEAC coefficient of 1.73.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Cobre/química , Cimenos/química , Compostos Heterocíclicos/química , Sulfetos/química , Cromanos/farmacologia , Estrutura Molecular
16.
Eur J Pharmacol ; 862: 172634, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494077

RESUMO

Flexible heteroarotinoids (Flex-Hets) are compounds with promising anti-cancer activities. SHetA2, a first-generation Flex-Het, has been shown to inhibit the growth of cervical, head and neck, kidney, lung, ovarian, prostate, and breast cancers. However, SHetA2's high lipophilicity, limited selectivity, low oral bioavailability, and complicated synthesis has led to the development of second-generation compounds, such as 1-(1-(naphthalen-1-yl)ethyl)-3-(4-nitrophenyl) thiourea or SL-1-09. Results from our lab show that SL-1-09 exhibits anti-cancer activities against ERα+ and ERα- breast cancer cells at micromolar concentrations. SL-1-09 is a mixture of two enantiomers, R and S. The objective of this study was to further analyze these enantiomers to determine their individual anti-cancer activities. Cell cycle analysis demonstrated that the percentage of cells in S-phase is reduced significantly when breast cancer cell lines MCF-7, T47D and MDA-MB-453 cells are treated with 5.0 µM of the S enantiomer. Consistent with this finding, treatment of these cells with the S enantiomer resulted in lower expression levels of cell cycle proteins. Overall, our data indicate that the S enantiomer shows greater growth inhibitory effects than the R form against ERα+ (MCF7 and T47D) and ERα- (MDA-MB-453) breast cancer cells, suggesting that the activity observed in SL-1-09 is most likely due to the ability of the S enantiomer to block cell cycle progression.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Cromanos/farmacologia , Tionas/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Cromanos/química , Cromanos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Estereoisomerismo , Tionas/química , Tionas/uso terapêutico
17.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
18.
Free Radic Biol Med ; 143: 140-145, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398499

RESUMO

Antibiotic resistance in bacteria is a serious threat to public health due to limited therapeutic options. Bactericidal agents with polypharmacological profiles or targeting bacterial membrane have lower propensity to develop resistance. Mitocurcumin (MitoC) is a novel compound synthesized by triphenyl-phosphonium conjugation with curcumin. Here, we demonstrate the antibacterial properties of MitoC that structurally differs markedly from the known antibacterial compounds. MitoC shows efficient bactericidal activity against Gram-positive and Gram-negative bacteria, including Mycobacteria, with MIC values in 1.5-12.5 µM range, but does not affect the viability of human leukocytes and human lung normal cell lines. Even at sub-MIC values, MitoC displays bactericidal properties. MitoC bactericidal action involves rapid disruption of bacterial membrane potential. Scanning electron microscope images of MitoC treated cells show structural deformations in terms of shrinking, loss of turgidity and formation of blisters and bubbles on their surface. Although MitoC increases ROS levels in bacterial cells, it may not be the primary cause of cell death as prior treatment with anti-oxidant trolox did not affect the MIC. This is the first report on bactericidal activity of MitoC and represents an excellent alternative for development of new generation bactericidal molecules that may be slow to develop resistance.


Assuntos
Antibacterianos/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Diarileptanoides/farmacologia , Animais , Antioxidantes/farmacologia , Bacillus subtilis/efeitos dos fármacos , Morte Celular , Linhagem Celular , Cromanos/farmacologia , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Potenciais da Membrana , Camundongos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Mycobacterium smegmatis/efeitos dos fármacos , Espécies Reativas de Oxigênio
19.
J Physiol Biochem ; 75(4): 499-517, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31414341

RESUMO

Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cromanos/farmacologia , Eugenol/análogos & derivados , Glioma/tratamento farmacológico , Vitamina E/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Eugenol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Vitamina E/farmacologia
20.
IUBMB Life ; 71(12): 1876-1895, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31359611

RESUMO

Redox imbalance due to hyperglycemia is a causative factor for an increased generation of reactive oxygen species (ROS) that leads to mitochondrial dysfunction and the release of cytochrome-c. The aim of the present study is to elucidate the functional role of oxidative stress (OS) in the induction of apoptosis in H9c2 cells in the hyperglycemic state through glucose transporter-4 (GLUT-4) regulation and antioxidant status. H9c2 cells were incubated with 15, 24, and 33 mM glucose for 24, 48, and 72 hr to induce hyperglycemic stress. Hyperglycemic episodes have significantly influenced GLUT-4 mRNA regulation, depleted glutathione (GSH) and its associated enzymes, reduced cellular antioxidant enzymes (AOEs), caused nuclear condensation, and induced apoptosis by activating caspase-9 and 3 and annexin V binding in a concentration and duration-dependent manner. Trolox pretreatment significantly enhanced the GLUT-4 mRNA and antioxidant defense mechanism, suppressed nuclear condensation, and prevented cytochrome-c release, thereby reducing mitochondrial-dependent apoptosis. The present study shows that the toxic effect of high glucose is significantly regulated and that OS induction can be prevented through a water-soluble vitamin E analog "Trolox" treatment.


Assuntos
Apoptose/efeitos dos fármacos , Cromanos/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/genética , Apoptose/fisiologia , Citocromos c/metabolismo , Enzimas/metabolismo , Glucose/efeitos adversos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Glutationa/metabolismo , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos
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