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1.
Molecules ; 26(22)2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34833894

RESUMO

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.


Assuntos
Ácidos Aminossalicílicos/farmacocinética , Ácidos Aminossalicílicos/toxicidade , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Ácidos Aminossalicílicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Feminino , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacocinética , Hidroxibenzoatos/toxicidade , Dose Letal Mediana , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
2.
Mar Drugs ; 19(5)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065505

RESUMO

Intestinal organoids can be used as an ex vivo epithelial model to study different drug delivery effects on epithelial cells' luminal surface. In this study, the impact of surface charge on the delivery of 5-ASA loaded PLGA nanoparticles into the lumen of organoids was investigated. Alginate and chitosan were used to coat the nanoparticles and provide negative and positive charges on the particles, respectively. The organoid growth and viability were not affected by the presence of either alginate- or chitosan-coated nanoparticles. It was shown that nanoparticles could be transported from the serosal side of the organoids to the lumen as the dye gradually accumulated in the lumen by day 2-3 after adding the nanoparticles to the Matrigel. By day 5, the dye was eliminated from the lumen of the organoids. It was concluded that the positively charged nanoparticles were more readily transported across the epithelium into the lumen. It may be attributed to the affinity of epithelial cells to the positive charge. Thus, the organoid can be utilized as an appropriate model to mimic the functions of the intestinal epithelium and can be used as a model to evaluate the benefits of nanoparticle-based drug delivery.


Assuntos
Alginatos/química , Quitosana/química , Intestino Delgado/citologia , Nanopartículas/química , Organoides/citologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Aminossalicílicos/química , Ácidos Aminossalicílicos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Técnicas In Vitro , Intestino Delgado/efeitos dos fármacos , Laminina , Camundongos , Microscopia , Microscopia Confocal , Microscopia de Fluorescência , Organoides/efeitos dos fármacos , Organoides/crescimento & desenvolvimento , Tamanho da Partícula , Proteoglicanas
3.
J Enzyme Inhib Med Chem ; 36(1): 410-424, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33440995

RESUMO

Twelve novel analogs of STAT3 inhibitor BP-1-102 were designed and synthesised with the aim to modify hydrophobic fragments of the molecules that are important for interaction with the STAT3 SH2 domain. The cytotoxic activity of the reference and novel compounds was evaluated using several human and two mouse cancer cell lines. BP-1-102 and its two analogs emerged as effective cytotoxic agents and were further tested in additional six human and two murine cancer cell lines, in all of which they manifested the cytotoxic effect in a micromolar range. Reference compound S3I-201.1066 was found ineffective in all tested cell lines, in contrast to formerly published data. The ability of selected BP-1-102 analogs to induce apoptosis and inhibition of STAT3 receptor-mediated phosphorylation was confirmed. The structure-activity relationship confirmed a demand for two hydrophobic substituents, i.e. the pentafluorophenyl moiety and another spatially bulky moiety, for effective cytotoxic activity and STAT3 inhibition.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Sulfonamidas/farmacologia , Ácidos Aminossalicílicos/síntese química , Ácidos Aminossalicílicos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
4.
Angew Chem Int Ed Engl ; 60(8): 3923-3927, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33325142

RESUMO

Olsalazine (Olsa) is a broad-spectrum anti-cancer agent acting as a DNA-methylation inhibitor. When conjugated to 2-cyano-6-aminobenzothiazole and a peptide substrate specific for the tumor-overexpressed enzyme furin, it can self-assemble into nanoparticles that can be detected by chemical-exchange saturation-transfer magnetic-resonance imaging (CEST MRI). We report here that these nano-assemblies can also be detected with high specificity in furin-overexpressing tumor cells by Raman spectroscopy with a distinct scattering signature and demonstrate the utility of this sensing mechanism in vitro and in vivo. Our findings suggest that Raman spectroscopy could be used for high-resolution image-guided surgery to precisely delineate tumor margins during and after resection in real-time as well as to determine microscopic tumor invasion and multifocal locoregional tumor spread, which are currently impossible to visualize with available imaging technologies, including CEST MRI.


Assuntos
Ácidos Aminossalicílicos/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Animais , Meios de Contraste/química , Células HCT116 , Humanos , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Neoplasias/patologia , Análise Espectral Raman , Transplante Heterólogo
6.
Nat Mater ; 18(12): 1376-1383, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636420

RESUMO

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent 'theranostic correlation' (R2 = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.


Assuntos
Ácidos Aminossalicílicos/metabolismo , Antineoplásicos/metabolismo , Furina/metabolismo , Espaço Intracelular/metabolismo , Imageamento por Ressonância Magnética/métodos , Nanopartículas , Ácidos Aminossalicílicos/química , Animais , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Células HCT116 , Humanos , Camundongos
7.
Pharmacol Rep ; 71(6): 1067-1078, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31627175

RESUMO

BACKGROUND: Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102. METHODS: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC-MS. RESULTS: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC-MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3. CONCLUSIONS: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.


Assuntos
Acetilcisteína/farmacologia , Ácidos Aminossalicílicos/farmacologia , Óxidos S-Cíclicos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/farmacologia , Ácidos Aminossalicílicos/química , Antraquinonas/química , Antraquinonas/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Óxidos S-Cíclicos/química , Humanos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sulfonamidas/química
8.
Biomolecules ; 9(8)2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412571

RESUMO

Improving the activity and selectivity profile of anticancer agents will require designing drug carrier systems that employ soluble macromolecules. Olsalazine-PAMAM-dendrimer-salicylic acid-conjugates with dendritic arms of different lengths have shown good stability regarding the chemical link between drug and spacer. In this study, the drug release was followed in vitro by ultraviolet (UV) studies. Evaluation of the cytotoxicity of the olsalazine-PAMAM-dendrimer-salicylic acid-conjugates employing a sulforhodamine B (SRB) assay in PC-3 (human prostatic adenocarcinoma) and MCF-7 (human mammary adenocarcinoma) cell lines demonstrated that conjugate 9 was more active as an antiproliferative agent than cisplatin, and no cytotoxicity towards the African green monkey kidney fibroblast (COS-7) cell line was observed in any of the conjugates synthesized in the present work.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Antineoplásicos/farmacologia , Dendrímeros/farmacologia , Ácido Salicílico/farmacologia , Ácidos Aminossalicílicos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células COS , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Dendrímeros/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ácido Salicílico/química , Solubilidade , Água/química
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 214: 531-536, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30818152

RESUMO

In this work, the supramolecular host-guest interaction of the prodrug Olsalazine (OLZ) and ß-Cyclodextrin (ß-CD) was examined experimentally and computationally. Experimentally, employing the UV-Vis spectroscopic method in aqueous media at various pH's, results obtained using the Benesi-Hilderbrand approach demonstrated that OLZ can form supramolecular inclusion complex with ß-CD with stoichiometric ratio of 1:1. Furthermore, these results revealed that the formation of OLZ: ß-CD complexes exhibited insignificant pH dependency in the range 5-8 with an average binding constant (Kb) of approximately 1×103M-1. Computationally, geometry optimization of 1:1 OLZ: ß-CD complexes was performed employing the ONIOM (DFT((ωB97XB)/6-31+G(d)),SQM(PM3)) approach. Obtained results demonstrated that OLZ: ß-CD complex is stabilized by the formation of intermolecular hydrogen bonds with an average length of approximately 1.8Å. Additionally, the stability of OLZ: ß-CD complex was demonstrated employing ADMP molecular dynamic simulations over a timeframe of 500fs. The molecularity of the supramolecular host-guest interaction between OLZ and ß-CD is presented and interpreted in the essence of TD-DFT and molecular orbitals analyses.


Assuntos
Ácidos Aminossalicílicos/química , Simulação de Dinâmica Molecular , beta-Ciclodextrinas/química
10.
Photochem Photobiol Sci ; 18(1): 166-176, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30397697

RESUMO

A novel multiple target sensor, (E)-5-((4-(diethylamino)-2-hydroxybenzyldene)amino)-1H-imidazole-4-carboxamide (DHIC), was synthesized for fluorescence detection of Zn2+ and S2- and colorimetric detection of Fe3+/2+ in aqueous media. DHIC can operate as a turn "on-off" sequential fluorescent sensor for Zn2+ and S2-. Detection limits (1.59 µM and 8.03 µM) for Zn2+ and S2- are below the WHO standards (76.0 µM and 14.7 µM). The DHIC-Zn2+ complex could be reversibly reused with ethylenediaminetetraacetic acid. Importantly, DHIC could image sequentially Zn2+ and S2- in living cells. Moreover, DHIC displayed a discriminatory color change from pale yellow to orange yellow to Fe3+/2+. The detection limit of DHIC for Fe3+/2+ (0.73 µM and 1.11 µM) is far below the EPA drinking water standard (5.37 µM). The sensor DHIC could be applied to analyze Fe3+ in real samples.


Assuntos
Técnicas Biossensoriais , Ferro/análise , Enxofre/análise , Zinco/análise , Ácidos Aminossalicílicos/química , Ácido Edético/química , Etilaminas/química , Fluorescência , Células HeLa , Humanos , Imidazóis/química , Ferro/química , Limite de Detecção , Metanol/química , Enxofre/química , Água/química , Zinco/química
11.
Molecules ; 23(7)2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973523

RESUMO

The antibacterial effects against Staphylococcus epidermidis of five silver carboxylate complexes with anti-inflammatory ligands were studied in order to analyze and compare them in terms of stability (in solution and after exposure to UV light), and their antibacterial and morphological differences. Four effects of the Ag-complexes were evidenced by transmission electronic microscopy (TEM) and scanning electronic microscopy (SEM): DNA condensation, membrane disruption, shedding of cytoplasmic material and silver compound microcrystal penetration of bacteria. 5-Chlorosalicylic acid (5Cl) and sodium 4-aminosalicylate (4A) were the most effective ligands for synthesizing silver complexes with high levels of antibacterial activity. However, Ag-5Cl was the most stable against exposure UV light (365 nm). Cytotoxic effects were tested against two kinds of eukaryotic cells: murine fibroblast cells (T10 1/2) and human epithelial ovarian cancer cells (A2780). The main objective was to identify changes in their antibacterial properties associated with potential decomposition and the implications for clinical applications.


Assuntos
Antibacterianos/síntese química , Complexos de Coordenação/síntese química , Prata/química , Staphylococcus epidermidis/efeitos dos fármacos , Ácidos Aminossalicílicos/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Estabilidade de Medicamentos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Salicilatos/química
12.
Nat Commun ; 8(1): 1130, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066712

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFß-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFß. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.


Assuntos
Fibrose/metabolismo , Fator de Transcrição STAT3/metabolismo , Escleroderma Sistêmico/metabolismo , Adolescente , Adulto , Idoso , Ácidos Aminossalicílicos/química , Animais , Benzenossulfonatos/química , Biópsia , Bleomicina/química , Colágeno/química , Ativação Enzimática , Feminino , Fibroblastos/metabolismo , Humanos , Inflamação , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Fosforilação , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
13.
ChemMedChem ; 12(21): 1739-1742, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-28901042

RESUMO

Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H4 olz), an anti-inflammatory compound used for treatment of ulcerative colitis. The materials include one-dimensional Ca(H2 olz)⋅4 H2 O chains, two-dimensional Ca(H2 olz)⋅2 H2 O sheets, and a three-dimensional metal-organic framework Ca(H2 olz)⋅2DMF (DMF=N,N-dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H2 olz) phase when exposed to aqueous HCl. The compounds Ca(H2 olz)⋅x H2 O (x=0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH-neutral intestines. All three calcium materials exhibited a delayed release of olsalazine relative to Na2 (H2 olz), the commercial formulation, illustrating how formulation of a drug within an extended coordination solid can serve to tune its solubility and performance.


Assuntos
Ácidos Aminossalicílicos/química , Cálcio/química , Complexos de Coordenação/química , Preparações de Ação Retardada , Portadores de Fármacos/química , Concentração de Íons de Hidrogênio
14.
Drug Deliv Transl Res ; 7(4): 571-581, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28290050

RESUMO

The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33-54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Micelas , Nanopartículas/administração & dosagem , Fator de Transcrição STAT3/antagonistas & inibidores , Ácidos Aminossalicílicos/administração & dosagem , Ácidos Aminossalicílicos/química , Ácidos Aminossalicílicos/farmacologia , Ácidos Aminossalicílicos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Dimerização , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Lactonas/administração & dosagem , Lactonas/química , Lactonas/farmacologia , Lactonas/uso terapêutico , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/uso terapêutico , Poliésteres/administração & dosagem , Poliésteres/química , Poliésteres/farmacologia , Poliésteres/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Solubilidade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
J Am Chem Soc ; 138(32): 10143-50, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27486905

RESUMO

The drug olsalazine (H4olz) was employed as a ligand to synthesize a new series of mesoporous metal-organic frameworks that are expanded analogues of the well-known M2(dobdc) materials (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M-MOF-74). The M2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 Å in diameter. Variable temperature H2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg2(olz) and Ni2(olz) were used to determine site-specific H2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg2(olz)(PEA)2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases.


Assuntos
Ácidos Aminossalicílicos/química , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Adsorção , Sítios de Ligação , Química Orgânica , Portadores de Fármacos , Gastroenteropatias/tratamento farmacológico , Humanos , Hidrogênio/química , Ligantes , Estruturas Metalorgânicas , Metais/química , Compostos Orgânicos/química , Fenetilaminas/química , Ácidos Ftálicos , Espectrofotometria Infravermelho , Propriedades de Superfície
16.
Chemosphere ; 154: 171-178, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27045634

RESUMO

Solutions of 100 mL with 1.20 mM of salicylic acid (SA), 4-aminosalicylic acid (4-ASA) or 5-aminosalicylic acid (5-ASA) have been comparatively degraded by anodic oxidation with electrogenerated H2O2 (AO-H2O2), electro-Fenton (EF) and photoelectro-Fenton (PEF). Trials were carried out with a stirred tank reactor with a BDD anode and an air-diffusion cathode for continuous H2O2 production. A marked influence of the functional groups of the drugs was observed in their decay kinetics, increasing in the order SA < 5-ASA < 4-ASA in AO-H2O2 and 5-ASA < SA < 4-ASA in EF and PEF, due to the different attack of OH generated at the BDD surface and in the bulk from Fenton's reaction, respectively. This effect was clearly observed when varying the current density between 16.7 and 100 mA cm(-2). The relative mineralization power of the processes always followed the sequence: AO-H2O2 < EF < PEF. The three drugs underwent analogous mineralization abatement up to 88% by AO-H2O2 at 100 mA cm(-2). The mineralization rate in EF and PEF grew in the order: 4-ASA < 5-ASA < SA. The most powerful process was PEF, attaining >98% mineralization for all the drugs at 100 mA cm(-2). Oxalic and oxamic acids were detected as final short-linear aliphatic carboxylic acids by ion-exclusion HPLC, allowing the fast photolysis of their Fe(III) complexes by UVA light to justify the high power of PEF.


Assuntos
Ácidos Aminossalicílicos/química , Ácidos Carboxílicos/análise , Peróxido de Hidrogênio/química , Ácido Oxálico/análise , Ácido Oxâmico/análise , Ácido Salicílico/química , Águas Residuárias/química , Poluentes Químicos da Água/química , Cromatografia Líquida de Alta Pressão , Eletrodos , Ferro/química , Cinética , Oxirredução , Fotólise , Águas Residuárias/análise
17.
Bioorg Med Chem Lett ; 26(9): 2152-5, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27025341

RESUMO

4-((3,5-Dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid (ZL006, 1) is a small-molecular inhibitor of the nNOS/PSD-95 interaction, that is under preclinical evaluation stage for cerebral ischemia. However, the fast metabolism and low permeability across the blood brain barrier (BBB) have restricted its further use. In this manuscript, the mass spectroscopy analysis showed that ZL006 mainly combined with glucuronic acid in mice plasma, which accelerated its metabolism and elimination. Hence, six ZL006 analogs were designed according to the probable metabolism sites of ZL006, and featured the alkylation at phenolic hydroxyl, secondary amine and carboxyl groups. These compounds were synthesized in moderate to good yields, and fully characterized with (1)H NMR and MS. Further metabolism investigation of ZL006 analogs showed that phenolic hydroxyl group of aromatic ring A was the major conjugation site with glucuronic acid, and ZL006 cyclohexyl ester (6) had a better permeability across BBB, which was a potent prodrug for cerebral ischemia.


Assuntos
Ácidos Aminossalicílicos/metabolismo , Benzilaminas/metabolismo , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pró-Fármacos/uso terapêutico , Ácidos Aminossalicílicos/química , Animais , Benzilaminas/química , Barreira Hematoencefálica/metabolismo , Esterificação , Glucuronídeos/metabolismo , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo
18.
Chemphyschem ; 17(6): 893-901, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26728445

RESUMO

Molecularly imprinted polymers (MIPs) are employed to screen nNOS-PSD-95 (neuronal nitric oxide synthase post-synaptic density protein-95) interruptions. 5-(3,5-Dichloro-2-hydroxybenzylamino)-2-hydroxybenzoic acid (ZL006; a potential drug candidate for the treatment of stroke, depression, and pain) is employed as a template. Four kinds of functional monomers (2-VP: 2-vinylpyridine; 4-VP: 4-vinylpyridine; MMA: methyl methacrylate; and MAAM: methacrylamide) are designed, and their complexation with ZL006 in various solvents (methanol, acetonitrile, toluene, chloroform) is investigated by molecular dynamics simulations and quantum mechanics calculations. Both 4-VP and MAAM have stronger interactions with ZL006 than those of 2-VP and MMA. The appropriate ratio of monomer to template is 3:1. Intermolecular hydrogen bonds play a dominant role in monomer-template complexation. Ideal solvents are toluene and chloroform, and the solvation effect on monomer-template complexation is revealed. Both molecular modeling and adsorption experiments demonstrate that as-synthesized ZL006-MIP with 4-VP as a monomer has better selectivity than that employing MAAM to screen for nNOS-PSD-95 interruptions.


Assuntos
Acrilamidas/química , Ácidos Aminossalicílicos/química , Benzilaminas/química , Peptídeos e Proteínas de Sinalização Intracelular/química , Metilmetacrilatos/química , Óxido Nítrico Sintase Tipo I/química , Piridinas/química , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Químicos , Simulação de Dinâmica Molecular , Impressão Molecular , Óxido Nítrico Sintase Tipo I/metabolismo , Teoria Quântica , Solventes
19.
Sci Rep ; 5: 12651, 2015 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26219474

RESUMO

The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Benzilaminas/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Sequência de Aminoácidos , Ácidos Aminossalicílicos/administração & dosagem , Ácidos Aminossalicílicos/química , Animais , Benzilaminas/administração & dosagem , Benzilaminas/química , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/complicações , Células Cultivadas , Células Endoteliais/metabolismo , Lipossomos/química , Lipossomos/farmacocinética , Lipossomos/ultraestrutura , Masculino , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Tamanho da Partícula , Peptídeos/administração & dosagem , Peptídeos/química , Polietilenoglicóis/química , Ratos Sprague-Dawley , Acidente Vascular Cerebral/etiologia , Distribuição Tecidual
20.
J Labelled Comp Radiopharm ; 58(8): 336-41, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26031480

RESUMO

Ulcerative colitis is a chronic disease having a regressive nature. Commonly used diagnostic methods have the disadvantage to be invasive, time-consuming, and expensive. Therefore, a new sensitive method for the detection and monitoring of disease activity is urgently needed in clinical practice. In the current investigation, radio complexation of olsalazine with technetium-99m, its characterization, and optimization of the labeling conditions were explored. Optimum radiochemical yield of (99m) Tc-olsalazine (97.6% ± 1.8%) was obtained via direct complexation with technetium-99m (~200 MBq) in the presence of stannous chloride dihydrate (100 µg) as reducing agent at pH 6. It was observed that the complex showed significant in vitro stability in serum at 37°C for more than 11 h. The computer-generated optimized geometries of the (99m) Tc-olsalazine were reported, and biodistribution studies were carried out using chemically and microbiologically mice-induced ulcerative colitis models. The tracer showed a good localization in both models and was excreted mainly via liver and to some extent via kidney. Imaging can be performed at 1-2 h post-injection; at that time, the background activity has cleared, and the activity is concentrated in the target site. All the gathered biological data supported the usefulness of (99m) Tc-olsalazine as a potential imaging agent for ulcerative colitis.


Assuntos
Ácidos Aminossalicílicos/farmacocinética , Anti-Inflamatórios não Esteroides/farmacocinética , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/patologia , Processamento de Imagem Assistida por Computador/métodos , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ácidos Aminossalicílicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Colite Ulcerativa/metabolismo , Marcação por Isótopo/métodos , Camundongos , Compostos de Organotecnécio/química , Cintilografia , Compostos Radiofarmacêuticos/química , Distribuição Tecidual
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