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1.
Chem Commun (Camb) ; 56(8): 1179-1182, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31868184

RESUMO

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Carboxílicos/farmacologia , Fulerenos/farmacologia , Água/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Fulerenos/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Solubilidade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
2.
J Agric Food Chem ; 67(49): 13534-13543, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718169

RESUMO

The fate of methiozolin under anaerobic conditions was investigated in clay loam with a high organic carbon content and sandy loam with a low carbon content using [dihydroisoxazole ring-14C] and [phenyl-14C] radiolabels. The sediment/water ratio was 1:3 based on the dry weight:volume (w/v) ratio; the incubations lasted up to 355 days after the treatment (DAT) and were performed in the dark at 20.4 ± 0.7 °C. The overlying water flow-through systems consisted of glass vessels containing sediment with traps for [14C]carbon dioxide and [14C]volatiles. The samples were collected and analyzed at 0, 3, 7, 14, 50, 100, 200, and 355 DAT. The water and sediment samples were extracted with solvent systems, centrifuged, concentrated, and analyzed by liquid scintillation counting and a high-performance liquid chromatography (HPLC) system equipped with a flow scintillation analyzer. Following extraction, the sediments were air-dried, and the subsamples were combusted. [14C]Methiozolin was degraded in the water phase and partitioned rapidly into the sediments, where it was further degraded to other metabolites, which were identified by HPLC and liquid chromatography- or gas chromatography-tandem mass spectrometry (MS/MS) with authentic standards. The dissipation of methiozolin from the overlying water was rapid (with half-lives of 1.1-1.8 and 3.6-4.9 days in the clay loam and sandy loam, respectively). However, methiozolin dissipation from the sediment phase and the whole system was much slower than from the water phase (with half-lives of 122.0-220.0 and 110.0-130.0 days in the sediment phase of the clay loam and sandy loam and 116.0-166.0 and 70.8-85.7 days in the whole system of the clay loam and sandy loam, respectively).


Assuntos
Radioisótopos de Carbono/análise , Sedimentos Geológicos/química , Isoxazóis/química , Tiofenos/química , Anaerobiose , Cromatografia Líquida de Alta Pressão , Argila/química , Cromatografia Gasosa-Espectrometria de Massas
3.
Inorg Chem ; 58(20): 14244-14259, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31595752

RESUMO

Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)2(dtdpq)](ClO4)2 (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)3](ClO4)2 (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH2Cl2 to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 106 M-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Luz , Fotoquimioterapia , Rutênio/farmacologia , Tiofenos/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Células HeLa , Humanos , Raios Infravermelhos , Células MCF-7 , Estrutura Molecular , Oxigênio/análise , Oxigênio/metabolismo , Rutênio/química , Tiofenos/química
4.
Chem Asian J ; 14(24): 4588-4593, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31608581

RESUMO

Typically, molecules with a twisted donor-acceptor (D-A) architecture have been exploited for constructing thermally activated delayed fluorescence (TADF) materials. Herein, we report the first example of a thiophene-based thermally activated delayed fluorescent molecule without a D-A architecture. Compound 1 (2,5-bis(2,2-di(thiophen-2-yl)vinyl)thiophene) is conformationally flexible and shows weak fluorescence in the solution state but displays bright TADFin both condensed and solid states. Compound 1 crystallized in two different polymorphs (1 a and 1 b). Interestingly, both polymorphs show distinctly different TADF features. The broad spectral features and the TADF characteristics of 1 have been explored for the time-dependent multicolor (green, yellow and red) imaging of living cells.


Assuntos
Corantes Fluorescentes/química , Tiofenos/química , Cor , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Imagem Óptica/métodos , Espectrometria de Fluorescência/métodos , Temperatura Ambiente , Tiofenos/síntese química
5.
Eur J Med Chem ; 183: 111676, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31542713

RESUMO

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.


Assuntos
Antiprotozoários , Flavonóis , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosforilcolina/análogos & derivados , Tiofenos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos/efeitos dos fármacos , Flavonóis/síntese química , Flavonóis/química , Flavonóis/farmacologia , Genômica , Humanos , Fosforilcolina/química , Fosforilcolina/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
6.
Chem Commun (Camb) ; 55(82): 12296-12299, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31536071

RESUMO

Controlling the behavior of mechanochromic luminescence (MCL) based on rational design principles is an outstanding challenge. Herein, an unprecedented self-recovering MCL that manifests in a large shift of the emission maximum (∼200 nm) has been achieved for 2-alkyl-4-(pyren-1-yl)thiophenes upon introducing long alkyl chains and mixing with N,N'-dimethylquinacridone.


Assuntos
Luminescência , Tiofenos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Espectrometria de Fluorescência
7.
Eur J Med Chem ; 183: 111690, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526973

RESUMO

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT7 and 5-HT1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT7R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT7R (Ki = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT7R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured Ki, further validating the quality of the models.


Assuntos
Pirimidinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
8.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480751

RESUMO

Biotransformations were performed on eight selected yeast strains, all of which were able to selectively hydrogenate the chalcone derivatives 3-(2"-furyl)- (1) and 3-(2"-thienyl)-1-(2'-hydroxyphenyl)-prop-2-en-1-one (3) into 3-(2"-furyl)- (2) and 3-(2"-thienyl)-1-(2'-hydroxyphenyl)-propan-1-one (4) respectively. The highest efficiency of hydrogenation of the double bond in the substrate 1 was observed in the cultures of Saccharomyces cerevisiae KCh 464 and Yarrowia lipolytica KCh 71 strains. The substrate was converted into the product with > 99% conversion just in six hours after biotransformation started. The compound containing the sulfur atom in its structure was most effectively transformed by the Yarrowia lipolytica KCh 71 culture strain (conversion > 99%, obtained after three hours of substrate incubation). Also, we observed that, different strains of tested yeasts are able to carry out the bioreduction of the used substrate with different yields, depending on the presence of induced and constitutive ene reductases in their cells. The biggest advantage of this process is the efficient production of one product, practically without the formation of side products.


Assuntos
Tiofenos/metabolismo , Leveduras/metabolismo , Biotransformação , Células Cultivadas , Chalconas/metabolismo , Hidrogenação , Especificidade por Substrato , Tiofenos/síntese química , Tiofenos/química
9.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
10.
Expert Opin Pharmacother ; 20(16): 1971-1980, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31424287

RESUMO

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.


Assuntos
Agonistas de Dopamina/uso terapêutico , Síndrome das Pernas Inquietas/tratamento farmacológico , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Agonistas de Dopamina/química , Agonistas de Dopamina/metabolismo , Gabapentina/química , Gabapentina/metabolismo , Gabapentina/uso terapêutico , Humanos , Pramipexol/química , Pramipexol/metabolismo , Pramipexol/uso terapêutico , Pregabalina/química , Pregabalina/metabolismo , Pregabalina/uso terapêutico , Síndrome das Pernas Inquietas/patologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/metabolismo , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/uso terapêutico , Topiramato/química , Topiramato/metabolismo , Topiramato/uso terapêutico
11.
Eur J Med Chem ; 182: 111603, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421633

RESUMO

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 µM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Compostos de Bifenilo/farmacologia , Desenho de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/química
12.
J Phys Chem Lett ; 10(18): 5292-5296, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31436425

RESUMO

Oligothiophenes have been established as important π-conjugated frameworks in organic electronics and molecular electronics. Although oligothiophenes possess the rotational flexibility of thiophene rings, the effects of cis-trans conformations on their electrical conductance have not been investigated yet. To investigate the effects of cis-trans conformations between thiophene rings on the conductance of oligothiophenes, we performed first-principles transport calculations. The conductance of the cis-oligothiophene was calculated to be higher than that of trans-oligothiophene, because the highest occupied molecular orbital was closer to the Fermi level of the gold electrode in the cis isomer than the trans isomer. This prediction was confirmed through mechanically controllable break junction measurements and fitting of the current-voltage characteristics for the newly synthesized, insulated oligothiophenes with controlled cis-trans conformations. This study demonstrates that cis- and trans-conformations can affect the electrical properties of oligothiophene frameworks and can potentially be used to control the electronic structure of long oligothiophene molecular wires.


Assuntos
Tiofenos/química , Teoria da Densidade Funcional , Condutividade Elétrica , Técnicas Eletroquímicas , Eletrodos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Propriedades de Superfície
13.
Eur J Med Chem ; 181: 111562, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377592

RESUMO

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.


Assuntos
Furanos/farmacologia , Compostos Heterocíclicos/farmacologia , Inflamação/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Carragenina/administração & dosagem , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Membro Posterior/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade , Tiofenos/química
14.
Chem Commun (Camb) ; 55(68): 10142-10145, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31389424

RESUMO

Hydrogen sulfide, an endogenous signalling molecule, is central to several pathophysiological processes in mammalian systems. It scavenges reactive oxygen species and is known to ameliorate dopaminergic neuronal degeneration in neurotoxin-induced Parkinson's disease models. The rapid volatilization of H2S from spontaneously releasing sulfide salts being a challenge, we describe peptide conjugates which exhibit tris(2-carboxyethyl)phosphine mediated "slow and sustained" H2S release. These conjugates reduced hydrogen peroxide-induced oxidative stress and significantly increased dopamine levels in transgenic C. elegans.


Assuntos
Dopamina/metabolismo , Sulfeto de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/farmacologia , Tionas/farmacologia , Tiofenos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Liberação Controlada de Fármacos , Oxirredução , Peptídeos/síntese química , Peptídeos/química , Fosfinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tionas/síntese química , Tionas/química , Tiofenos/síntese química , Tiofenos/química , alfa-Sinucleína/genética
15.
Nanoscale ; 11(32): 15195-15205, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31380883

RESUMO

Mimicking the hierarchical microarchitecture of native myocardium in vitro plays an important role in cardiac tissue engineering. Here we present a novel strategy to produce multiscale conductive scaffolds with layer-specific fiber orientations for cardiac regeneration by combining solution-based and melt-based electrohydrodynamic (EHD) printing techniques. Polycaprolactone (PCL) microfibers were printed by melt-based EHD printing and the fiber orientation was flexibly controlled in a layer-by-layer manner according to user-specific design. The as-printed microfibrous scaffolds can provide the seeded cells necessary contact cues to guide layer-specific cellular alignments. Sub-microscale conductive fibers were simultaneously incorporated inside the well-organized PCL scaffolds by solution-based EHD printing, which significantly improved the conductivity as well as the cellular adhesion and proliferation capacity. The multiscale conductive scaffolds can further direct the multiple-layer alignments of primary cardiomyocytes and facilitate cardiomyocyte-specific gene expressions, which exhibited enhanced synchronous beating behavior compared with pure microfibrous scaffolds. It is envisioned that the proposed hybrid EHD printing technique might provide a promising strategy to fabricate multifunctional micro/nanofibrous scaffolds with biomimetic architectures, electrical conductivity and even biosensing properties for the regeneration of electroactive tissues.


Assuntos
Impressão Tridimensional , Engenharia Tecidual , Tecidos Suporte/química , Animais , Adesão Celular , Proliferação de Células , Células Cultivadas , Condutividade Elétrica , Microscopia de Fluorescência , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Nanofibras/química , Poliésteres/química , Poliestirenos/química , Ratos , Ratos Sprague-Dawley , Tiofenos/química
16.
Nanoscale ; 11(29): 13947-13960, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31305836

RESUMO

Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. These particles were determined to have a diameter of ∼115 nm, with a polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 cells determined through flow cytometry showed a ∼5-fold increase between untargeted and HA-coated particles. Through viability and DNA damage assays, we assessed the potency of the free RTX and HARPs, and found increased DNA damage in cells treated with the RTX-loaded nanoparticles administered concurrently with radiation. In vivo efficacy through tumor growth inhibition was investigated in a syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute toxicity in vivo, and all treatments showed survival benefits for their respective groups compared to controls. HARPs alone slowed tumor growth, although not significantly. Radiation alone and in combination with the HARPs showed significant growth delay. Notably, the combination treatment significantly hindered tumor progression relative to the HARPs highlighting the benefit of this multipronged treatment. These results provide a foundation for loading RTX in a nanoparticle formulation, and establish a combined radiation and drug dosing schedule to determine optimal tumor growth delay and subsequent treatment efficacy.


Assuntos
Antimetabólitos Antineoplásicos/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Quinazolinas/química , Tiofenos/química , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Dano ao DNA/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Radiação Ionizante , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Transplante Heterólogo
17.
Eur J Med Chem ; 180: 72-85, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301565

RESUMO

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/farmacologia , Tiofenos/farmacologia , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/administração & dosagem , Pirazóis/química , Relação Estrutura-Atividade , Tiofenos/administração & dosagem , Tiofenos/química , Células Tumorais Cultivadas
18.
Pak J Pharm Sci ; 32(3): 963-967, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278707

RESUMO

A new series of copper (II), cobalt (II), zinc (II), nickel (II), manganese (II), iron (II) complexes with a novel Schiff base were synthesized by the condensation of sulphadizine and thiophene-2-carbaldehyde.The ligand and its complexes were characterized by using diverse instrumental procedures like microanalysis, thermo gravimetric examination and spectroscopy. The integrated ligand and its metal complexes were subjected to antibacterial studies. These studies demonstrated the enhanced activity of metal complexes against reported microbes with respect to the Schiff base.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Metais/química , Anti-Infecciosos/química , Bacillus pumilus/efeitos dos fármacos , Clostridium butyricum/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Enterobacter aerogenes/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella oxytoca/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Staphylococcus aureus/efeitos dos fármacos , Tiofenos/química
20.
Phys Chem Chem Phys ; 21(31): 17410-17422, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31359017

RESUMO

We report on accurate and efficient calculations of vibrationally resolved emission spectra for oligothiophenes from anharmonic vibrational configuration interaction wave-function calculations in reduced vibrational spaces. These reduced spaces are chosen based on the independent mode displaced harmonic oscillator model. Good agreement with experiment is obtained for all-trans oligothiophenes with two to five rings also when employing only a few active modes. Vibrational modes incorporating inter-ring carbon-carbon stretches and a ring breathing mode are found to be the main players in the vibrational progression for the emission from the first excited electronic state for all investigated oligothiophene derivatives. The presented framework is here illustrated for oligothiophenes, but we have made no underlying system-dependent assumptions and believe it to become a valuable tool for the rational design of fluorescence biomarkers.


Assuntos
Corantes Fluorescentes/química , Modelos Moleculares , Tiofenos/química , Conformação Molecular , Teoria Quântica , Espectrometria de Fluorescência/métodos , Termodinâmica , Vibração
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