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1.
Sci Rep ; 10(1): 7635, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376987

RESUMO

Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.


Assuntos
Vírus da Influenza A/crescimento & desenvolvimento , Compostos Organosselênicos , Serina Endopeptidases/genética , Linhagem Celular , Pegada de DNA , Descoberta de Drogas , Quadruplex G , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Vírus da Influenza A/fisiologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Regiões Promotoras Genéticas , Transcrição Genética
2.
Chemistry ; 26(5): 1127-1135, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31721326

RESUMO

Non-invasive theranostics that integrate the advantages of multimodality imaging and therapeutics have great potential in the field of biomedicine. Herein, a new nanohybrid based on Bi2 Se3 -conjugated upconversion nanoparticles (UCNPs) has been successfully developed through a simple in situ growth strategy. Under 808 nm near-infrared laser irradiation, the UCNPs can emit bright visible light, whereas the Bi2 Se3 nanomaterial exhibits efficient photothermal conversion capacity. Moreover, the as-synthesized UCNP-Bi2 Se3 nanohybrid exhibits efficient cell upconversion luminescence (UCL), reasonable CT imaging, and admirable cancer cell ablation capacity, further emphasizing the efficiency of this strategy for simultaneous UCL imaging and photothermal therapy. The designed theranostic strategy guided by dual-modal imaging endowed with real-time dynamic monitoring, remote controllability, and non-invasiveness makes the UCNP-Bi2 Se3 nanohybrid an ideal candidate for non-invasive multimodal imaging-guided photothermal therapy for the precise diagnosis and treatment of cancer.


Assuntos
Meios de Contraste/química , Nanopartículas Metálicas/química , Compostos Organosselênicos/química , Tomografia Computadorizada por Raios X , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Endocitose/efeitos dos fármacos , Humanos , Luz , Nanopartículas Metálicas/toxicidade , Microscopia de Fluorescência , Neoplasias/patologia , Neoplasias/terapia , Fototerapia
3.
Cell Mol Life Sci ; 77(8): 1623-1643, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31378829

RESUMO

The pathophysiology of type 2 diabetes mellitus (T2D) is characterized by reduced or absent insulin receptor (INSR) responsiveness to its ligand, elevated hepatic glucose output and impaired glucose uptake in peripheral tissues, particularly skeletal muscle. Treatments to reduce hyperglycemia and reestablish normal insulin signaling are much sought after. Any agent which could be orally administered to restore INSR function, in an insulin-independent manner, would have major implications for the management of this global disease. We have discovered a non-peptidyl small molecule, adenosine, 5'-Se-methyl-5'-seleno-, 2',3'-diacetate [referred to as non-peptidyl compound #43 (NPC43)], which restores INSR signaling in the complete absence of insulin. Initial screening of numerous compounds in human HepG2 liver cells revealed that NPC43 significantly inhibited glucose production. The compound was potently anti-hyperglycemic and anti-hyperinsulinemic in vivo, in insulin-resistant T2D Leprdb/db mice, following either acute or chronic treatment by oral gavage and intraperitoneal injection, respectively. The compound acted at the level of INSR and activated it in both liver and skeletal muscle of Leprdb/db mice. In cell culture, the compound activated INSR in both liver and skeletal muscle cells; furthermore, it cooperated with insulin to depress glucose-6-phosphatase catalytic subunit (G6pc) expression and stimulate glucose uptake, respectively. Our results indicated that the compound directly interacted with INSRα, triggering appropriate phosphorylation and activation of the receptor and its downstream targets. Unlike insulin, NPC43 did not activate insulin-like growth factor 1 receptor in either liver or skeletal muscle. We believe this compound represents a potential oral and/or injectable insulin replacement therapy for diabetes and diseases associated with insulin resistance.


Assuntos
Adenosina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Receptor de Insulina/metabolismo , Adenosina/análogos & derivados , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Células Hep G2 , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipoglicemiantes/química , Insulina/metabolismo , Resistência à Insulina , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organosselênicos/química , Compostos Organosselênicos/uso terapêutico
4.
Mater Sci Eng C Mater Biol Appl ; 106: 110152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753399

RESUMO

In the current study, organoruthenium(II)-arene complexes (I-IV) have been prepared by the reaction of [{(η6-p-cym)RuCl}2(µ-Cl)2] with new thiosemicarbazones (TSC1-4).The isolate was analyzed using elemental analysis, FT-IR, 1H and 13C NMR spectroscopy and single-crystal XRD. Subsequently, the complexes and TSC ligands were assessed for anticancer properties in vitro against three different colorectal cancer stage's cell lines (Caco-2, DLD-1, and SW620) and a noncancerous cell line (CCD18Co). The complexes (I-IV) showed higher cytotoxicity with low IC50 values as 0.1-0.33 µM in colorectal cell lines except for SW620 (47.4-84.20 µM) than in a noncancerous cell. Complex I was 2.8 and 24.5-fold more active against Caco-2 and DLD-1 than CCD18Co, respectively. The complexes (I-IV) accumulated at a high concentration in the cell nuclei and caused cell cycle arrest by affecting the G0/G1 and/or G2/M phase and showed high binding affinity with CT-DNA (Kb = 104 M-1). The expression of Caspase-3 and Caspase-9 apoptosis-related protein levels was slightly upregulated and Atg5 autophagy-related protein level was clearly downregulated according to control and 5-FU-treated cells after complex I and II treatment. Furthermore, it was observed that cytotoxicity of the complexes is decreased while cancer progresses. Altogether, this study indicates that all organoruthenium (II)-arene complexes (particularly complex I) can be a promising alternative to platinum counterparts in cancer treatment.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/síntese química , Compostos Organosselênicos/química , Tiossemicarbazonas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Proteína 5 Relacionada à Autofagia/metabolismo , Caspase 3/metabolismo , Bovinos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Ligação Proteica , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
Chem Commun (Camb) ; 56(2): 179-196, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31782422

RESUMO

Organo-seleno compounds (org-Se) have been widely used in antitumor, antiviral, and antiinflammatory therapy; antioxidation and other biological fields. As such, they have made an important contribution to overcoming various kinds of diseases, and researchers are increasingly attracted to org-Se's synthesis and functional design. This review is mainly focused on the design and synthesis of various kinds of org-Se, followed by their anticancer mechanisms such as the mitochondria mediated pathway induced by ROS, death receptor mediated pathways involving p53 phosphorylation, and the activation of the AMPK pathway to promote apoptosis. Org-Se also serves as a sensitizer in chemotherapy and radiotherapy, and an antagonist against the cytotoxic effects induced by chemotherapeutic agents. Finally, we will summarize the development of cancer-targeted org-Se containing complexes, and nanotechnology-based org-Se for anticancer application. This review could provide information for the future design of chemically innovative org-Se with anticancer potential, and shed light on the discovery of nanomaterial-based pharmaceuticals to improve drug development and formation.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Desenho de Fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas/química , Neoplasias/radioterapia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Morte Celular/metabolismo , Proteína Supressora de Tumor p53/metabolismo
6.
Sensors (Basel) ; 19(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627267

RESUMO

In-liquid biosensing is the new frontier of health and environment monitoring. A growing number of analytes and biomarkers of interest correlated to different diseases have been found, and the miniaturized devices belonging to the class of biosensors represent an accurate and cost-effective solution to obtaining their recognition. In this study, we investigate the effect of the solvent and of the substrate modification on thin films of organic semiconductor Poly(3-hexylthiophene) (P3HT) in order to improve the stability and electrical properties of an Electrolyte Gated Organic Field Effect Transistor (EGOFET) biosensor. The studied surface is the relevant interface between the P3HT and the electrolyte acting as gate dielectric for in-liquid detection of an analyte. Atomic Force Microscopy (AFM) and X-ray Photoelectron Spectroscopy (XPS) characterizations were employed to study the effect of two solvents (toluene and 1,2-dichlorobenzene) and of a commercial adhesion promoter (Ti Prime) on the morphological structure and electronic properties of P3HT film. Combining the results from these surface characterizations with electrical measurements, we investigate the changes on the EGOFET performances and stability in deionized (DI) water with an Ag/AgCl gate electrode.


Assuntos
Técnicas Biossensoriais , Monitoramento Ambiental , Compostos Organosselênicos/química , Solventes/química , Eletrodos , Microscopia de Força Atômica , Semicondutores , Propriedades de Superfície , Água/química
7.
Colloids Surf B Biointerfaces ; 184: 110546, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606701

RESUMO

CD47, a transmembrane protein overexpressed in most tumors, limits macrophage phagocytosis by interacting with macrophage signal-regulated protein α (SIRPα). In this study, we have developed CD47-targeted bismuth selenide nanoparticles (Ab-PEG-Bi2Se3) that increase phagocytosis of cancer cells by macrophages to actualize improved photothermal therapy (PTT). The functionalized nanoparticles were constructed by conjugating anti-CD47 antibody (Ab) to PEGylated bismuth selenide nanoparticles (PEG-Bi2Se3). The anti-CD47 antibody modified on the nanoparticles enhanced the phagocytic activity of macrophages toward tumor cells by specifically blocking the crosstalk between CD47 and SIRPα. Meanwhile, Ab-PEG-Bi2Se3 showed excellent photothermal performance including strong near infrared (NIR) absorbance, high photothermal conversion efficiency and photostability, and exhibited outstanding in vitro PTT effect under NIR laser irradiation. In vivo therapeutic experiments revealed that this CD47-targeted PTT nanoagent, with the assistance of enhanced macrophage phagocytosis, achieved the goal of tumor eradication. Besides, toxicity studies confirmed that Ab-PEG-Bi2Se3 had good biocompatibility. In conclusion, Ab-PEG-Bi2Se3 may serve as an efficient PTT platform in combination with macrophage-mediated immunotherapy to improve antitumor efficacy.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas/química , Compostos Organosselênicos/farmacologia , Fotoquimioterapia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antígeno CD47 , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Raios Infravermelhos , Macrófagos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Propriedades de Superfície , Células Tumorais Cultivadas
8.
Int J Biol Macromol ; 141: 529-537, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493457

RESUMO

Selenium is an essential trace element in human body, and kappa-selenocarrageenan (Se-car) is an organic source of selenium supplement. To further utilize Se-car in food packaging, biotherapy or biosensor, the molecular information of Se-car was characterized here and multi-functional Ag NPs synthesized by Se-car were fabricated. Results of GPC-MALLS, FTIR, potentiometric titration, and intrinsic viscosity showed that Se-car was polymerized by nearly 22 basic units of disaccharide. Sixty-four percentage of sulfated groups (SO42-) in carrageenan was replaced by selenium acid (SeO32-), which belonged to weak acid resulting from a gradually decrease of ζ-potential with acidity process to pH 1.0. Besides, the capacity of biosynthesis silver nanoparticles (Ag NPs) by Se-car was studied and it made a comparison with κ-carrageenan. Results exhibited that Se-car could serve as an efficient reducing and capping agent for Ag NPs fabrication (remarked as Se-car@Ag). The kapp of Se-car@Ag NPs for catalyzing 4-NP degradation was 2.14 × 10-2 s-1. Antibacterial test revealed Se-car@Ag had an ability to inhibit the growth of Escherichia coli and Staphylococcus aureus. To combine the selenium health benefit and functional metal nanoparticles, Se-car@Ag might have potential applications in multiple areas like medicine, disease diagnostic, and drug delivery.


Assuntos
Antibacterianos , Carragenina/química , Escherichia coli/crescimento & desenvolvimento , Química Verde , Nanopartículas Metálicas/química , Compostos Organosselênicos/química , Prata , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Prata/química , Prata/farmacologia
9.
Molecules ; 24(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405214

RESUMO

A series of variously functionalized selenium-containing compounds were purposely synthesized and evaluated against a panel of cancer cell lines. Most of the compounds showed an interesting cytotoxicity profile with compound 5 showing a potent activity on MCF7 cells. The ethyl amino derivative 5 acts synergistically with cis-platin and inhibits the GST enzyme with a potency that well correlates with the cytotoxicity observed in MCF7 cells. A computational analysis suggests a possible binding mode on the GST enzyme. As the main outcome of the present study, the ethyl amino derivative 5 emerged as a valid lead compound for further, future developments.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos , Glutationa Transferase/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Compostos Organosselênicos , Compostos de Selênio , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Células K562 , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos de Selênio/síntese química , Compostos de Selênio/química , Compostos de Selênio/farmacologia
10.
Carbohydr Polym ; 223: 115070, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31427031

RESUMO

A biodegradable, near-infrared (NIR) - responsive hydrogel is one of the most promising strategies as a remotely triggered drug carrier. In this study, novel NIR-responsive hydrogels based on alginate structures were prepared for controllable drug release. The hydrogels were formed rapidly by reacting norbornene-functionalized alginates and tetrazine cross-linkers containing diselenide bonds via inverse electron demand Diels-Alder click chemistry. In order to manipulate their properties, we prepared hydrogels with various cross-linking densities. NIR sensitive indocyanine green (ICG) and a drug, doxorubicin (DOX) were incorporated in the hydrogel matrix during gelation. The hydrogels showed a suppressed release profile under physiological conditions, while NIR light triggered a rapid release of DOX. Under NIR-light irradiation, ICG generated reactive oxygen species which could decompose diselenide bonds in the hydrogel matrix, inducing the gel-sol transition and release of entrapped DOX. The degradation of hydrogels could be also controlled by the ratio of the precursors.


Assuntos
Alginatos/química , Portadores de Fármacos/química , Hidrogéis/química , Compostos Organosselênicos/química , Alginatos/síntese química , Alginatos/efeitos da radiação , Doxorrubicina/química , Portadores de Fármacos/efeitos da radiação , Liberação Controlada de Fármacos , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/efeitos da radiação , Hidrogéis/síntese química , Hidrogéis/efeitos da radiação , Peróxido de Hidrogênio/química , Raios Infravermelhos , Norbornanos/síntese química , Norbornanos/química , Norbornanos/efeitos da radiação , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/efeitos da radiação
11.
Chem Commun (Camb) ; 55(69): 10214-10217, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380528

RESUMO

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.


Assuntos
Azóis/química , Azóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cisteína/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
12.
Eur J Med Chem ; 179: 515-526, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276896

RESUMO

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células MCF-7 , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Picratos/antagonistas & inibidores , Picratos/metabolismo , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 179: 557-566, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276900

RESUMO

Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, ß-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe its multiple roles, we ran a high-throughput drug repurposing screening. Ebselen, cefmetazole and rabeprazole were identified as reversible inhibitors of IDE. Ebselen is the most potent inhibitor (IC50(insulin) = 14 nM). The molecular mode of action of ebselen was investigated by biophysical methods. We show that ebselen induces the disorder of the IDE catalytic cleft, which significantly differs from the previously reported IDE inhibitors. IDE inhibition by ebselen can explain some of its reported activities in metabolism as well as in neuroprotection.


Assuntos
Azóis/farmacologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Insulisina/antagonistas & inibidores , Compostos Organosselênicos/farmacologia , Azóis/química , Biocatálise , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Humanos , Insulisina/metabolismo , Estrutura Molecular , Compostos Organosselênicos/química , Relação Estrutura-Atividade
14.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277425

RESUMO

The reactions of 3-isoselenocyanato-2,2,5,5-tetramethylpyrrolidine-1-oxyl, 3-isoselenocyanatomethyl-2,2,5,5-tetramethyl-3-pyrrolidine-1-oxyl, and 4-isoselenocyanato-2,2,6,6-tetramethylpiperidine-1-oxyl with selected amines and alcohols give the corresponding novel nitroxyl selenoureas and selenocarbamates, all bearing a nitroxyl moiety. Synthesized selenoureas and selenocarbamates show significant activity against pathogenic fungi and bacteria. In contrast to piperidine nitroxides, pyrrolidine, five-membered nitroxyl selenoureas and selenocarbamates show excellent antifungal and antibacterial activity against pathogenic fungi and bacteria, respectively.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Carbamatos/farmacologia , Óxidos de Nitrogênio/síntese química , Óxidos de Nitrogênio/farmacologia , Compostos Organosselênicos/farmacologia , Ureia/análogos & derivados , Bactérias/efeitos dos fármacos , Carbamatos/síntese química , Carbamatos/química , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Óxidos de Nitrogênio/química , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Ureia/síntese química , Ureia/química , Ureia/farmacologia
15.
J Trace Elem Med Biol ; 55: 180-189, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345356

RESUMO

BACKGROUND: Gliomas are the most aggressive malignant tumors of the central nervous system. The diphenyl diselenide [(PhSe)2] is an organoselenium compound that has multiple pharmacological properties. Previous reports showed that (PhSe)2 nanoencapsulation potentiates its in vitro antitumoral action and reduces its toxicity. OBJECTIVE: In this sense, the current study was designed to further evaluate the (PhSe)2 antitumoral effect by a set of in vitro techniques using a glioma cell line as well as by an animal model of gliobastoma. METHODS: For the in vitro tests, the cell viability, propidium iodide uptake and nitrite levels of rat glioma C6 cells were determined after incubation with free (PhSe)2 or (PhSe)2-loaded nanocapsules (NC). The glioblastoma model was induced by implantation of C6 glioma cells in the right striatum of rats. Following, animals were submitted to a repeated intragastric administration treatment with (PhSe)2 or NC (PhSe)2 (1 mg/kg/day for 15 days) to assess the possible antitumor effect. MAIN FINDINGS: Both compound forms decreased the C6 glioma cells viability without causing any effect in astrocytes cells (healthy control). Importantly, the NC (PhSe)2 had superior cytotoxic effect than its free form and increased the nitrite content. Independent of the (PhSe)2 forms, the intragastric treatment reduced brain tumor size and caused neither alteration in the plasma renal and hepatic markers of function nor in the parameters of oxidative balance in brain, liver and kidneys. PRINCIPAL CONCLUSIONS: The (PhSe)2 nanoencapsulation improved its cytotoxic effect against C6 glioma cells and both compound forms attenuated the tumor development.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Nanocápsulas/química , Compostos Organosselênicos/farmacologia , Animais , Antineoplásicos/química , Astrócitos/efeitos dos fármacos , Derivados de Benzeno/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Masculino , Nitritos/análise , Compostos Organosselênicos/química , Ratos , Ratos Wistar
16.
J Trace Elem Med Biol ; 55: 64-70, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345368

RESUMO

BACKGROUND: Patients with metabolic bone diseases often have high risk of titanium implant failure due to compromised bone regeneration ability. Clinical evidence indicates that the poor osteogenic ability is partly because of excessive oxidative stress. To date, specific treatments for these patients are urgently needed. Ebselen, a non-toxic organoselenium compound, is reported to be a potent antioxidant agent. In this study, we hypothesized that ebselen exerted protective effects on osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. METHODS: BMSCs were isolated from SD rats, and their morphology and multiple differentiation abilities were characterized. Proliferation rates of BMSCs treated with different concentrations of ebselen were analyzed. Then BMSCs were pretreated by hydrogen peroxide (H2O2), after which ebselen at different concentrations (0, 1, 5, 10 µM) was added, alkaline phosphatase (ALP) activity, mineralization and osteogenic-related protein levels were evaluated and an optimum concentration of ebselen was selected. Subsequently, intracellular reactive oxygen species (ROS) generation and the role of the PI3K/AKT pathway were also investigated. RESULTS: Ebselen within a proper range could promote the proliferation of BMSCs. H2O2-induced oxidative stress suppressed osteogenic differentiation of BMSCs, which was verified by the decrease in ALP activity, calcium deposition, Runx2 and ß-catenin expression. However, ebselen could alleviate osteogenic dysfunction of BMSCs. We also observed that ebselen reduced ROS accumulation in H2O2-pretreated BMSCs. Moreover, the pro-osteogenic effects afforded by ebselen were almost abolished by the Akt inhibitor. CONCLUSION: We concluded that ebselen could attenuate osteogenic dysfunction of BMSCs induced by H2O2 through an antioxidant effect and the activation of the PI3K/Akt pathway, suggesting that ebselen has a potential therapeutic effect for patients with metabolic bone diseases.


Assuntos
Antioxidantes/farmacologia , Azóis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Osteogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antioxidantes/química , Azóis/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Compostos Organosselênicos/química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
17.
J Trace Elem Med Biol ; 55: 78-81, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345370

RESUMO

SCOPE: Selenoneine (2-selenyl-Nα, Nα, Nα-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. METHODS AND RESULTS: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h post-treatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. CONCLUSION: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.


Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Histidina/análogos & derivados , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peróxidos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/química , Relação Dose-Resposta a Droga , Histidina/química , Histidina/farmacologia , Estrutura Molecular , Compostos Organosselênicos/química , Peróxidos/farmacologia , Substâncias Protetoras/química , Relação Estrutura-Atividade
18.
J Phys Chem A ; 123(28): 5995-6002, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31268326

RESUMO

High-resolution X-ray crystallography and two-dimensional NMR studies demonstrate that water-mediated conventional hydrogen-bonding interactions (N-H···N, O-H···N, etc.) bridging two or more amino acid residues contribute to the stability of proteins and protein-ligand complexes. In this work, we have investigated single water-mediated selenium hydrogen-bonding interactions (unconventional hydrogen-bonding) between amino acid residues in proteins through extensive protein data bank (PDB) analysis coupled with gas-phase spectroscopy and quantum chemical calculation of a model complex consisting of indole, dimethyl selenide, and water. Here, indole and dimethyl selenide represent the amino acid residues tryptophan and selenomethionine, respectively. The current investigation demonstrates that the most stable structure of the model complex observed in the IR spectroscopy mimics single water-mediated selenium hydrogen-bonded structural motifs present in the crystal structures of proteins. The present work establishes that water-mediated Se hydrogen-bonding interactions are ubiquitous in proteins and the number of these interactions observed in the PDB is more than that of direct Se hydrogen-bonds present there.


Assuntos
Proteínas/química , Selênio/química , Água/química , Biologia Computacional , Cristalografia por Raios X , Bases de Dados de Proteínas , Ligação de Hidrogênio , Indóis/química , Ligantes , Modelos Moleculares , Compostos Organosselênicos/química , Teoria Quântica , Selenometionina/química , Espectrofotometria Infravermelho , Triptofano/química
19.
PLoS One ; 14(7): e0219664, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31310642

RESUMO

Phenylalanine and cysteine comprise common miss-sense variants (i.e., single nucleotide polymorphisms [SNPs]) at amino acid position 254 of the human indole(ethyl)amine-N-methyltransferase (hINMT). The phenylalanine variant, which occurs in linkage disequilibrium with two 3' UTR SNPs, has been reported to associate with elevated urine levels of trimethylselenonium (TMSe), the Se-methylated product of volatile dimethylselenide. hINMT allozymes expressing either cysteine (254C) or phenylalanine (254F) at position 254 were compared for enzyme activity (i.e., Km and Vmax) towards the INMT substrates tryptamine, dimethylsulfide (DMS) and dimethylselenide (DMSe) in vitro. The SNP 254C had a higher Vmax for DMS and tryptamine in the presence of reducing agent than in its absence. Conversely, Vmax for 254F was insensitive to the presence or absence of reducing agent for these substrates. SNP 254F showed a lower Km for tryptamine in the absence of reducing agent than 254C. No statistically significant difference in Vmax or Km was observed between 254C and 254F allozymes in the presence of reducing agent for DMSe, The Km values for DMSe methylation were about 10-fold (254C) or 6-fold (254F) more favorable than for tryptamine methylation with reducing agent present. These findings indicated that: 1) That phenylalanine at position 254 renders hINMT methylation of substrates DMS and tryptamine insensitive to a non reducing environment. 2) That human INMT harbors significant thioether-S-methyltransferase (TEMT) activity with a higher affinity for DMSe than tryptamine, 3) The reduction of a 44C/254C disulfide bond in hINMT that increases Vmax is proposed.


Assuntos
Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Compostos Organosselênicos/química , Sulfetos/química , Triptaminas/química , Alelos , Cristalografia por Raios X , Dissulfetos , Escherichia coli , Humanos , Isoenzimas , Cinética , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Conformação Proteica
20.
Eur J Med Chem ; 179: 493-501, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271961

RESUMO

Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action. A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance. In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea. Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Compostos Organosselênicos/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade
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