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1.
Top Curr Chem (Cham) ; 377(6): 37, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31728771

RESUMO

Over the past decade, the combination of visible light photocatalysis and organocatalysis has made remarkable progress in modern chemical synthesis. In these dual catalysis system, photocatalysts or photosensitizers absorb visible light to induce their photoexcited states which can activate unreactive substrates via electron or energy transfer mechanisms, and organocatalysts are usually employed to regulate the chemical reactivity of the other substrates. By doing so, two reactive species react with each in a selective-especially enantioselective-way, to provide the final products. This article summarizes the recent development of cooperative catalysis by the combination of organocatalysis and photocatalysis in asymmetric organic synthesis. These reactions are classified according to the manner of activation of the organocatalysts. Enamine/iminium catalysts are used to activate unreactive carbonyl molecules. Nucleophilic catalysts including nitrogen heterocycle carbene catalysts and tertiary amine catalysts are employed to reverse the reactivity of electrodeficient substrates including aldehydes and enals. Chiral Brønsted acid catalysts are used to activate substrates by forming key H-bonding complexes between substrates and catalysts.


Assuntos
Aminas/química , Iminas/química , Luz , Aldeídos/química , Alcenos/química , Catálise , Metano/análogos & derivados , Metano/química , Estereoisomerismo
2.
Phys Chem Chem Phys ; 21(42): 23408-23417, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31625550

RESUMO

In the field of artificial metalloenzyme (ArM) catalysis, how to identify the critical factors affecting the catalytic activity and enantioselectivity remains a challenge. In this work, the mechanism of enantioselective reduction of imine catalyzed by using [Rh(Me4Cpbiot)Cl2]·S112H Sav (denoted as S112H) and [Rh(Me4Cpbiot)Cl2]·K121H Sav (denoted as K121H) was studied by using molecular dynamics (MD) simulations combined with density functional theory (DFT) calculations. Four binding modes of imine, two proton sources (hydronium ion and lysine) and eight proposed reaction pathways were systematically discussed. The results showed that due to the anchoring effect of the mutation site of ArMs, the rhodium complex which oscillated like a pendulum was bound to a specific conformation, which further determined the chirality of the reduced product. C-Hπ, cation-π and ππ weak interactions played an important role in imine binding, and the favorable binding mode of imine was catalyzed by S112H in landscape orientation and catalyzed by K121H in portrait orientation, respectively. LYS121 is the most possible proton source in the S112H catalytic process while the proton source in the K121H catalytic process is the hydronium ion of the active sites. Furthermore, based on the reaction mechanism, modification of Rh(Me4Cpbiot)Cl2 was carried out in S112H and K121H, and the results suggested that the reaction barrier could be effectively reduced by replacing the methyl groups on Cp* with an amino group. This work gives a fundamental understanding of the mechanism of ArMs toward the imine reduction reaction, in the hope of providing a strategy for reasonable designs of ArMs with high enantioselectivity.


Assuntos
Complexos de Coordenação/química , Iminas/química , Sítios de Ligação , Catálise , Domínio Catalítico , Complexos de Coordenação/metabolismo , Teoria da Densidade Funcional , Metaloproteínas/química , Metaloproteínas/metabolismo , Simulação de Dinâmica Molecular , Oxirredução , Ródio/química , Estereoisomerismo , Termodinâmica
3.
Chem Biodivers ; 16(11): e1900413, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31503399

RESUMO

The synthesis of sulfenimines and sulfinimines has been carried out with 10-hydroxyisocamphylthiol. The configuration of the compounds has been deduced by methods of NMR, DFT calculations and X-ray diffraction analysis. The cytotoxic, antioxidant and membrane-protective activity of the synthesized compounds as well as of the previously obtained sulfenimines and sulfinimines based on 4-caranethiol have been determined.


Assuntos
Antioxidantes/farmacologia , Iminas/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , /química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Humanos , Iminas/síntese química , Iminas/química , Estrutura Molecular , Relação Estrutura-Atividade
4.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480760

RESUMO

A synthetic approach to a new group of stable chiral C2-symmetric diimines with the 4,5-diazafluorene core has been developed based on condensation of dipinodiazafluorene with aromatic diamines. The chemical structures of new compounds were proven by spectroscopic methods and X-ray crystallography. All the compounds form solvates with organic solvents (chloroform, benzene, 1,4-dioxane) and water. Specific spectral data of the new compounds are explained using calculated data (DFT). Diimines of the pinodiazafluorene series give colored reactions with transition metal ions and can be regarded as prospective polydentate ligands with interesting luminescent and chiroptical properties.


Assuntos
Fluorenos/química , Iminas/química , Cristalografia por Raios X , Iminas/síntese química , Luminescência , Conformação Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo , Temperatura Ambiente
5.
Chem Biol Interact ; 311: 108789, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401089

RESUMO

The cytotoxicity of a dinuclear imine-copper (II) complex 2, and its analogous mononuclear complex 1, toward different melanoma cells, particularly human SKMEL-05 and SKMEL-147, was investigated. Complex 2, a tyrosinase mimic, showed much higher activity in comparison to complex 1, and its reactivity was verified to be remarkably activated by UVB-light, while the mononuclear compound showed a small or negligible effect. Further, a significant dependence on the melanin content in the tumor cells, both from intrinsic pigmentation or stimulated by irradiation, was observed in the case of complex 2. Similar tests with keratinocytes and melanocytes indicated a much lower sensitivity to both copper (II) complexes, even after exposition to UV light. Clonogenic assays attested that the fractions of melanoma cells survival were much lower under treatment with complex 2 compared to complex 1, both with or without previous irradiation of the cells. The process also involves generation of reactive oxygen species (ROS), as verified by EPR spectroscopy, and by using fluorescence indicators. Autophagic assays indicated a remarkable formation of cytoplasmic vacuoles in melanomas treated with complex 2, while this effect was not observed in similar treatment with complex 1. Monitoring of specific protein LC3 corroborated the simultaneous occurrence of autophagy. A balance interplay between different modes of cell death, apoptosis and autophagy, occurs when melanomas were treated with the dinuclear complex 2, in contrast to the mononuclear complex 1. These results pointed out to different mechanisms of action of such complexes, depending on its nuclearity.


Assuntos
Complexos de Coordenação/química , Cobre/química , Iminas/química , Monofenol Mono-Oxigenase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Humanos , Melaninas/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/metabolismo , Raios Ultravioleta
6.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366120

RESUMO

The chiral structure of antibiotic vancomycin (Van) was exploited as an innovative coordination sphere for the preparation of an IrCp* based hybrid catalysts. We found that Van is able to coordinate iridium (Ir(III)) and the complexation was demonstrated by several analytical techniques such as MALDI-TOF, UV, Circular dichroism (CD), Raman IR, and NMR. The hybrid system so obtained was employed in the Asymmetric Transfer Hydrogenation (ATH) of cyclic imines allowing to obtain a valuable 61% e.e. (R) in the asymmetric reduction of quinaldine 2. The catalytic system exhibited a saturation kinetics with a calculated efficiency of Kcat/KM = 0.688 h-1mM-1.


Assuntos
Antibacterianos/química , Complexos de Coordenação/química , Iminas/química , Irídio/química , Vancomicina/química , Catálise , Hidrogenação , Cinética , Oxirredução , Quinaldinas/química , Estereoisomerismo
7.
Molecules ; 24(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319634

RESUMO

In the present study, 4-methylpyridin-2-amine was reacted with 3-bromothiophene-2-carbaldehyde and the Schiff base (E)-1-(3-bromothiophen-2-yl)-N-(4-methylpyridin-2-yl)methanimine was obtained in a 79% yield. Coupling of the Schiff base with aryl/het-aryl boronic acids under Suzuki coupling reaction conditions, using Pd(PPh3)4 as catalyst, yielded products with the hydrolysis of the imine linkages (5a-5k, 6a-6h) in good to moderate yields. To gain mechanistic insight into the transition metal-catalyzed hydrolysis of the compounds, density functional theory (DFT) calculations were performed. The theoretical calculations strongly supported the experiment and provided an insight into the transition metal-catalyzed hydrolysis of imines.


Assuntos
Iminas/química , Piridinas/química , Catálise , Hidrólise , Iminas/síntese química , Modelos Moleculares , Estrutura Molecular , Nitrogênio/química , Paládio/química , Piridinas/síntese química , Bases de Schiff/química
8.
Eur J Med Chem ; 179: 404-422, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265934

RESUMO

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ±â€¯1.7 µM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.


Assuntos
Acetilcolinesterase/metabolismo , Amidas/farmacologia , Inibidores da Colinesterase/farmacologia , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Amidas/química , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Iminas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Eur J Pharm Biopharm ; 142: 92-100, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176724

RESUMO

HYPOTHESIS: Because of its hydrophilic character the peptide drug Polymyxin B (PMB) cannot be incorporated in lipophilic nanocarrier systems such as self-emulsifying drug delivery systems (SEDDS) for oral administration. Due to the formation of imine conjugates between the primary amino groups of PMB and the carbonyl group of cinnamaldehyde, however, drug lipophilicity might be sufficiently raised for incorporation in SEDDS. METHODS: Imine bonds were formed between the primary amino groups of PMB and the carbonyl group of cinnamaldehyde. PMB-cinnamaldehyde conjugate was characterized regarding degree of substitution, log P and release of PMB due to interaction with bovine serum albumin (BSA), SEDDS loading and cell viability. RESULTS: 87.1% of primary amines formed imines with cinnamaldehyde. Log P was increased 69.183 - folds. BSA triggered release of PMB was 45.2%, 64.9% and 80.6% within 16 h. Log DSEDDS/Release medium of PMB-cinnamaldehyde conjugate was 3.4. CONCLUSION: According to these findings, the concept of imine bond formation with cinnamaldehyde can be considered as a novel concept for increasing lipophilicity of the hydrophilic antibiotic peptide PMB.


Assuntos
Emulsões/química , Iminas/química , Peptídeos/química , Administração Oral , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Emulsificantes/administração & dosagem , Emulsificantes/química , Emulsões/administração & dosagem , Humanos , Interações Hidrofóbicas e Hidrofílicas , Iminas/administração & dosagem , Peptídeos/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/química , Solubilidade/efeitos dos fármacos
10.
J Colloid Interface Sci ; 553: 71-82, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31200231

RESUMO

Cellulose nanocrystals (CNCs) are promising bio-derived nanomaterials for the bottom-up fabrication of biomedical constructs. In this report, dicarboxylic acid-functionalized CNC (DCC) was functionalized with arginylglycylaspartic acid (RGD) tripeptide as a motif for improved cell adhesion and targeting. The product (DCC-RGD) self-assembled into a more elongated nanofibrillar structure through lateral and end-to-end association. When added into poly(ethylene imine) (PEI)/pDNA polyplex solution, nanocelluloses interacted electrostatically with positively charged polyplexes without affecting their integrity. The constructs were tested for their potentials as non-viral transfection reagents. Cell viability and transfection efficiency of fibroblast NIH3T3 cells were monitored as a function of CNC concentration where, in general, viability increased as the CNC concentration increased, and transfection efficiency could be optimized. Using wild-type MDCK and αV-knockout MDCK cells, the construct was able to provide targeted uptake of polyplexes. The findings have potential applications, for example, cell-selective in vitro or ex vivo transfection of autologous mesenchymal stem cells for cell therapy, or bottom-up design of future innovative biomaterials.


Assuntos
Celulose/química , DNA/química , Iminas/química , Nanofibras/química , Nanopartículas/química , Oligopeptídeos/química , Polietilenos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Cães , Relação Dose-Resposta a Droga , Células Madin Darby de Rim Canino , Camundongos , Estrutura Molecular , Células NIH 3T3 , Oligopeptídeos/farmacologia , Tamanho da Partícula , Plasmídeos , Propriedades de Superfície
11.
Mar Drugs ; 17(6)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200525

RESUMO

On our quest for new bioactive molecules from marine sources, two cyclic imines (1, 2) were isolated from a dinoflagellate extract, inhibiting the growth of the respiratory syncytial virus (RSV). Compound 1 was identified as a known molecule portimine, while 2 was elucidated to be a new cyclic imine, named kabirimine. The absolute stereochemistry of 1 was determined by crystallographic work and chiral derivatization, whereas the structure of 2 was elucidated by means of spectroscopic analysis and computational study on all the possible isomers. Compound 1 showed potent cytotoxicity (CC50 < 0.097 µM) against HEp2 cells, while 2 exhibited moderate antiviral activity against RSV with IC50 = 4.20 µM (95% CI 3.31-5.33).


Assuntos
Dinoflagelados/química , Iminas/química , Antivirais/química , Antivirais/farmacologia , Organismos Aquáticos/química , Linhagem Celular Tumoral , Humanos , Iminas/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos
12.
J Colloid Interface Sci ; 550: 81-89, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31055140

RESUMO

Soft nanoparticles have attracted increasing attention in biomedical fields because of their unique biological behaviors such as long circulation and high cellular uptake. However, previously reported soft nanoparticles are generally spherical or torispherical in shape, and non-spherical soft nanoparticles are rarely reported because of the shape is thermodynamically unstable for typical soft materials (e.g., liposomes and micelles). Herein, soft mesoporous organosilica nanorods with gold plasmonic core protected with poly-ethylene imine (GNR@SMON/PEI) have been successfully synthesized, for the first time, by a dispersive-protection etching method, in which rod-like solid mesoporous organosilicas with gold nanorod are firstly shielded with PEI (GNR@MON/PEI) and then etched with aqueous NaOH solution. The prepared GNR@SMON/PEI inherits the rod morphology of the mother particle, showing wrinkled morphology and excellent dispersity thanks to the dispersive-protection effect of PEI. In addition, the GNR@SMON/PEI possesses a uniform size (174 × 105 nm), well-defined mesopores (3.9 nm), high surface area (355 m2/g) and large pore volume (0.35 m3/g). Notably, the soft GNR@SMON/PEI exhibits significantly lower Young's modulus (120.2 MPa) in contrast with the hard counterpart (361.4 MPa). Furthermore, after being decorated with hyaluronic acid (HA), the soft GNR@SMON/PEI-HA exhibits excellent in vitro and in vivo biocompatibility. The soft GNR@SMON/PEI-HA has achieved 3-fold cellular uptake efficiency in contrast with the hard one, indicating great potential for biomedical applications. Taken together, this work reports the controllable synthesis of a soft mesoporous nanorod with high cellular uptake efficiency, providing a vital strategy for the synthesis of non-spherical soft nanoparticles and a new nanoplatform for various biomedical applications in future.


Assuntos
Materiais Biocompatíveis/química , Ouro/química , Nanocompostos/química , Nanotubos/química , Compostos de Organossilício/química , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Fluoresceína-5-Isotiocianato/química , Humanos , Ácido Hialurônico/química , Iminas/química , Células MCF-7 , Tamanho da Partícula , Polietilenos/química , Porosidade , Propriedades de Superfície
13.
Arch Pharm (Weinheim) ; 352(6): e1800358, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066103

RESUMO

Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)-piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 µg/ml). Compound R7 was found to be moderately active with an IC50 of 2.1 ± 0.04 µM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Antituberculosos/farmacologia , Desenho de Drogas , Iminas/farmacologia , Tuberculose/tratamento farmacológico , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antituberculosos/síntese química , Antituberculosos/química , Simulação por Computador , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Iminas/síntese química , Iminas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia
14.
Water Sci Technol ; 79(6): 1092-1101, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31070589

RESUMO

The present study is focused on the removal of Hg2+, Cd2+ and Pb2+ ions from aqueous solution using a tridentate chelating agent, 2-pyridyl-N-(2'-methylthiophenyl) methyleneimine (PMTPM); and applicability of such removal from industrial wastewater using PMTPM is also investigated. The results showed that the metal ions removal efficiency using PMTPM was in the order of Hg2+(99.46%) > Cd2+(95.42%) > Pb2+(94.54%) under optimum reaction conditions (L:M2+ = 3:1, pH = 9, time = 24 h, temp. = 30 °C). Formed chelated complexes such as [Hg(PMTPM)Cl2] (1), [Cd(PMTPM)Cl2] (2) and [Pb(PMTPM)Cl2] (3) were characterized by numerous spectroscopic tools and X-ray structure determination of a representative complex of Hg2+. In the X-ray structure of [Hg(PMTPM)Cl2], 1, the Hg2+ adopted a distorted tetrahedral coordination geometry surrounding two N donors of PMTPM and two chloride ions. A similar coordination geometry surrounding the respective metal centres in 2 and 3 was established. The thermogravimetric analysis (TGA) revealed a stability order of [Cd(PMTPM)Cl2] > [Hg(PMTPM)Cl2] > [Pb(PMTPM)Cl2]. Further the comparative metal leaching behaviour of these chelate complexes exhibited higher stability in alkaline solution than in acidic. Moreover, PMTPM was applied in real mixed industrial wastewater with alkaline pH, and adequate removals of toxic metals were achieved.


Assuntos
Metais Pesados/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Cádmio/análise , Cádmio/química , Quelantes , Cristalografia por Raios X , Iminas/química , Chumbo/análise , Chumbo/química , Mercúrio/análise , Mercúrio/química , Metais Pesados/análise , Águas Residuárias , Poluentes Químicos da Água/análise
15.
J Recept Signal Transduct Res ; 39(1): 55-59, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31132911

RESUMO

The NAD+-dependent histone deacetylase SIRT1 was shown to be associated with aging and longevity. A stilbene, resveratrol (RV) was shown to exert anti-aging activity by stimulating the SIRT1 activity. However, the utility of RV is limited by its low bioavailability and structural instability. It is thus envisaged to test imine stilbene (IMS) analogs of RV for their potential anti-aging activity. In the present study, molecular docking analysis of five IMS analogs (3a, 3b, 3c, 3d and 3e) against the SIRT1 protein has been carried out. All the five IMS analogs displayed enhanced binding affinity towards SIRT1; three out of five IMS analogs (3a, 3 b, 3e) showed significantly higher affinity with lower binding energies (-9.58, -9.54, and -9.82 kcal mol-1) than RV (-8.11 kcal mol-1). Further, experimental validation of anti-aging activity was performed by measuring the chronological life span in vitro using yeast and cellular replicative senescence (CRS) in mammalian cell line models. All IMS analogs extended the chronological life span in yeast as compared to untreated cells as well as RV treated cells. Enhanced anti-aging activity was also observed in an analogous mammalian cell line model upon treatment with either RV or IMS analogs. The results thus suggest that most of the IMS analogs tested may serve as potent drug lead molecules with anti-aging activity.


Assuntos
Senescência Celular/efeitos dos fármacos , Iminas/química , Longevidade , Resveratrol/farmacologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Sirtuína 1/metabolismo , Estilbenos/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/efeitos dos fármacos
16.
J Mater Sci Mater Med ; 30(6): 58, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127370

RESUMO

Clinical application of cisplatin (CDDP) against various solid tumors is often limited due to its poor selectivity and severe side effect. Considering this, in our study, CDDP was incorporated in fluorescent PEG amine grafted aldehyde hyaluronic acid by imine bond and metal ion coordination bond linking and formed a complex, the complex was then self-assembled into nanoparticles in water simply. FT-IR, XRD, DLS and SEM analysis demonstrated that the nanoparticles were prepared successfully and exhibited a spherical structure with size ranged from 216.4 to 372.3 nm in diameter. CDDP releasing from the nanoparticles was in a controlled manner, and had faster release rate at lower pH, indicating the nanoparticles were responsive to tumor micro-acid environment. Since fluorescent Cy5.5 and targeting hyaluronic acid existed on the surface of the nanoparticles, CLSM images clearly showed that the nanoparticles could target and internalize into HeLa cells, and then inhibited the growth of HeLa cells. In addition, MTT, AO-EB staining, and hemolysis assay showed that the nanoparticles had good cyto-/hemo-compatibility. Hence, the nanoparticles had the potential to be used for cancer therapy and diagnosis. The further in vivo experiment will be shown in the next work. pH responsible and fluorescent Cy5.5-PEG-g-A-HA/CDDP complex nanoparticles were facilely fabricated for controlled and targeted delivery of CDDP.


Assuntos
Cisplatino/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polietilenoglicóis/química , Aldeídos/química , Antineoplásicos/administração & dosagem , Carbocianinas/química , Linhagem Celular Tumoral , Portadores de Fármacos , Corantes Fluorescentes/química , Células HeLa , Hemólise , Humanos , Concentração de Íons de Hidrogênio , Iminas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
17.
Eur J Med Chem ; 174: 116-129, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029943

RESUMO

The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50 = 8.3 ±â€¯0.3 µM; Ki 5.2 µM). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step.


Assuntos
Acetilcolinesterase/metabolismo , Benzamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Iminas/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/química , Benzamidas/síntese química , Benzamidas/química , Benzamidas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Humanos , Iminas/síntese química , Iminas/química , Iminas/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Relação Estrutura-Atividade
18.
Org Lett ; 21(8): 2855-2858, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30933523

RESUMO

Furylimines of aromatic o-nitro aldehydes undergo a photoinduced cascade transformation offering rapid atom- and step-economical access to complex polyheterocyclic scaffolds possessing a privileged pyrroloquinazolinone core.


Assuntos
Alcaloides/química , Pirróis/química , Quinazolinonas/química , Aldeídos/química , Catálise , Ciclização , Iminas/química , Oxirredução , Processos Fotoquímicos , Polímeros/química , Estereoisomerismo
19.
Inorg Chem ; 58(9): 5956-5965, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30986046

RESUMO

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-ß-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh3) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Iminas/química , Irídio/química , Rutênio/química , Células A549 , Aminação , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Células HeLa , Células Hep G2 , Humanos , Iminas/síntese química , Iminas/farmacologia , Irídio/farmacologia , Modelos Moleculares , Neoplasias/tratamento farmacológico , Rutênio/farmacologia
20.
J Colloid Interface Sci ; 549: 72-79, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022525

RESUMO

Overuse and abuse of antibiotics greatly hasten the development of microbial drug resistance and substantially threat to global public health. Developing alternative methods for combating bacterial infections is urgently required. In this work, a simple hydrothermal approach was employed to prepare the protoporphyrin IX-polyethylenimine nanoparticles (PPIX-PEI NPs) containing abundant amine groups and PPIX moieties. The as-obtained PPIX-PEI NPs exhibit antibacterial properties against both Gram-positive and Gram-negative bacteria. The presence of PPIX in the PPIX-PEI NPs can generate reactive oxygen species (ROS) under 635 nm laser irradiation, which enhance the antibacterial properties of the PPIX-PEI NPs against Gram-positive bacteria. Thus, the PPIX-PEI NPs display a synergistic antibacterial activity against Gram-positive bacteria in the combination of antibacterial photodynamic therapy (PDT). In addition, emission of red fluorescence by the PPIX-PEI NPs can help to differentiate bacteria and observe the bacterial morphologies using a confocal laser scanning microscope (CLSM).


Assuntos
Antibacterianos/química , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Antibacterianos/farmacologia , Corantes Fluorescentes/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Humanos , Iminas/química , Imagem Óptica/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Polietilenos/química , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
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