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1.
PLoS One ; 15(5): e0233591, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453773

RESUMO

The heart is critically dependent on mitochondrial respiration for energy supply. Ischemia decreases oxygen availability, with catastrophic consequences for cellular energy systems. After a few minutes of ischemia, the mitochondrial respiratory chain halts, ATP levels drop and ion gradients across cell membranes collapse. Activation of cellular proteases and generation of reactive oxygen species by mitochondria during ischemia alter mitochondrial membrane permeability, causing mitochondrial swelling and fragmentation and eventually cell death. The mitochondria, therefore, are important targets of cardioprotection against ischemic injury. We have previously shown that ixazomib (IXA), a proteasome inhibitor used for treating multiple myeloma, effectively reduced the size of the infarct produced by global ischemia in isolated rat hearts and prevented degradation of the sarcoplasmic reticulum calcium release channel RyR2. The aim of this work was to further characterize the protective effect of IXA by determining its effect on mitochondrial morphology and function after ischemia. We also quantified the effect of IXA on levels of mitofusin-2, a protein involved in maintaining mitochondrial morphology and mitochondria-SR communication. We found that mitochondria were significantly preserved and functional parameters such as oxygen consumption, the ability to generate a membrane potential, and glutathione content were improved in mitochondria isolated from hearts perfused with IXA prior to ischemia. IXA also blocked the release of cytochrome c observed in ischemia and significantly preserved mitofusin-2 integrity. These beneficial effects resulted in a significant decrease in the left ventricular end diastolic pressure upon reperfusion and a smaller infarct in isolated hearts.


Assuntos
Compostos de Boro/farmacologia , Glicina/análogos & derivados , Coração/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Animais , Quimotripsina/farmacologia , Modelos Animais de Doenças , Glutationa/genética , Glutationa/metabolismo , Glicina/farmacologia , Coração/fisiopatologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/fisiopatologia , Consumo de Oxigênio/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Ratos
2.
Org Biomol Chem ; 18(13): 2416-2431, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186571

RESUMO

A synthetic strategy to BODIPY dyes is presented giving access to a range of new compounds relevant in the context of antimicrobial photodynamic therapy (aPDT). BODIPYs with the 8-(4-fluoro-3-nitrophenyl) and the 8-pentafluorophenyl substituents were used for the synthesis of new mono- and dibrominated BODIPYs. The para-fluorine atoms in these electron-withdrawing groups facilitate functional modification via nucleophilic aromatic substitution (SNAr) with a number of amines and thio-carbohydrates. Subsequently, the antibacterial phototoxic activity of these BODIPYs has been assessed in bacterial assays against the Gram-positive germ S. aureus and also against the Gram-negative germ P. aeruginosa. The bacterial assays allowed to identify substitution patterns which ensured antibacterial activity not only in phosphate-buffered saline (PBS) but also in the presence of serum, hereby more realistically modelling the complex biological environment that is present in clinical applications.


Assuntos
Antibacterianos/farmacologia , Compostos de Boro/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antibacterianos/síntese química , Antibacterianos/efeitos da radiação , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Luz , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
3.
Sci Adv ; 6(4): eaaz1722, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010792

RESUMO

In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.


Assuntos
Compostos de Boro/farmacologia , Terapia por Captura de Nêutron de Boro , Metabolismo Energético/efeitos dos fármacos , Fenilalanina/análogos & derivados , Álcool de Polivinil/farmacologia , Radiossensibilizantes/farmacologia , Animais , Compostos de Boro/química , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Espectrometria de Massas , Camundongos , Neoplasias/terapia , Fenilalanina/química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Álcool de Polivinil/química , Álcool de Polivinil/farmacocinética , Radiossensibilizantes/química , Radiossensibilizantes/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Med Chem ; 63(6): 3104-3119, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32031798

RESUMO

Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Endopeptidase Clp/antagonistas & inibidores , Peptidomiméticos/uso terapêutico , Inibidores de Serino Proteinase/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Compostos de Boro/farmacologia , Ácidos Borônicos/metabolismo , Ácidos Borônicos/farmacologia , Endopeptidase Clp/metabolismo , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacologia , Ligação Proteica , Inibidores de Serino Proteinase/metabolismo , Inibidores de Serino Proteinase/farmacologia , Pele/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Virulência/efeitos dos fármacos
5.
Sci Rep ; 10(1): 3080, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080210

RESUMO

We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1-2.3] vs. 3.5 months [95% CI, 1.7-5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8-9.8] vs. 12.7 months [95% CI, 7.1-18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Mutação/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Proteína Supressora de Tumor p53/genética , Vorinostat/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacologia , Glicina/efeitos adversos , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Resultado do Tratamento , Vorinostat/efeitos adversos , Vorinostat/farmacologia , Adulto Jovem
6.
Chem Commun (Camb) ; 56(13): 1956-1959, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-31956868

RESUMO

Herein, we report a pH stimulus-disaggregated BODIPY sensitizer (PTS) with low background-toxicity for achieving activated photodynamic/photothermal tumor therapy. Both the photodynamic and photothermal properties of PTS can be activated under acidic conditions, and PTS exhibits excellent antitumor properties, which is revealed by both in vitro and in vivo tests.


Assuntos
Compostos de Boro/química , Fármacos Fotossensibilizantes/química , Animais , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Luz , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Transplante Heterólogo
7.
J Med Chem ; 63(4): 1699-1708, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31967820

RESUMO

Singlet oxygen can severely damage biological tissue, which is exploited in photodynamic therapy (PDT). In PDT, the effective range is limited by the distribution of the photosensitizer (PS) and the illuminated area. However, no distinction is made between healthy and pathological tissue, which can cause undesired damage. This encouraged us to exploit the more acidic pH of cancerous tissue and design pH-controllable singlet oxygen-generating boron-dipyrromethene (BODIPY) dyes. A pH sensitivity of the dyes is achieved by the introduction of an electronically decoupled, photoinduced electron transfer (PET)-capable subunit in meso-position of the BODIPY core. To favor triplet-state formation as required for singlet oxygen generation, iodine substituents were introduced at the chromophore core. The resulting pH-controlled singlet oxygen-generating dyes with pKa values in the physiological range were subsequently assessed regarding their potential as pH-controlled PS for PDT. Using HeLa cells, we could successfully demonstrate markedly different pH-dependent cytotoxicities upon illumination.


Assuntos
Compostos de Boro/farmacologia , Corantes Fluorescentes/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/metabolismo , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Luz , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Nanomedicina Teranóstica
8.
J Drugs Dermatol ; 19(1): 50-64, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31985912

RESUMO

Approval of the new topical phosphodiesterase 4 inhibitor crisaborole ointment, 2%, to treat mild-to-moderate atopic dermatitis (AD) warrants careful consideration of available efficacy and safety data for topical therapies to contribute to a better understanding of the role of crisaborole in the treatment of mild-to-moderate AD. A literature review was conducted to identify results of randomized, blinded, vehicle-controlled trials of topical agents for the treatment of AD published from January 1, 1997 to April 30, 2018. This review summarizes the efficacy and safety data of topical therapies including corticosteroids, calcineurin inhibitors, and crisaborole and it shows that comparison among available agents is difficult because of differing methodologies used across clinical trials and that there is considerable variability in safety reporting among AD trials. Published clinical studies for crisaborole demonstrate its efficacy and manageable safety profile. J Drugs Dermatol. 2020;19(1):50-64. doi:10.36849/JDD.2020.4508


Assuntos
Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Administração Cutânea , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Dermatite Atópica/patologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Humanos , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
9.
Nanotechnology ; 31(21): 215101, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31978926

RESUMO

The molecular stress caused by a drug administered to treat a disorder on healthy cells appears as a side effect. In this study, we aim to understand the potential of hexagonal boron nitrides (hBNs) as a therapeutic agent to relieve the cellular stress exerted by drugs. First, the cytotoxicity of hBNs and their possible degradation product, boric acid (BA), on the embryonic mouse hippocampal cell line mHippo E-14 was assessed in a wide concentration range (4.4-440 µg ml-1) of boron including hBNs and BA for 24 and 72 h exposure. Then, cell cycle, reactive oxygen species generation, cell death mechanism and apoptotic body formation in nuclei with hBN and BA exposure were evaluated at increased concentrations and incubation times. Finally, the cells, exposed to doxorubicin (DOX), an anti-cancer chemotherapy drug, to exert oxidative stress, were treated with hBNs and BA. The results indicate that hBNs decrease the oxidative stress at the concentrations that are nontoxic to cells. The study suggests that hBNs can open new venues for their investigation to reduce or eliminate the adverse effects of toxic drugs used in the treatment of several fatal diseases including neurological disorders and cancer with their slow degradation feature.


Assuntos
Compostos de Boro/farmacologia , Doxorrubicina/efeitos adversos , Hipocampo/embriologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Nanoestruturas , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo
10.
Life Sci ; 241: 117116, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790690

RESUMO

AIMS: LexA protein is a transcriptional repressor which regulates the expression of more than 60 genes belonging to the SOS global regulatory network activated by damages to bacterial DNA. Considering its role in bacteria, LexA represents a key target to counteract bacterial resistance: the possibility to modulate SOS response through the inhibition of LexA autoproteolysis may lead to reduced drug susceptibility and acquisition of resistance in bacteria. In our study we investigated boron-containing compounds as potential inhibitors of LexA self-cleavage. MAIN METHODS: The inhibition of LexA self-cleavage was evaluated by following the variation of the first-order rate constant by LC-MS at several concentrations of inhibitors. In silico analysis was applied to predict the binding orientations assumed by the inhibitors in the protein active site, upon covalent binding to the catalytic Ser-119. Bacterial filamentation assay was used to confirm the ability of (3-aminophenyl)boronic acid to interfere with SOS induced activation. KEY FINDINGS: Boron-containing compounds act as inhibitors of LexA self-cleavage, as also confirmed by molecular modelling where the compounds interact with the catalytic Ser-119, via the formation of an acyl-enzyme intermediate. A new equation for the description of the inhibition potency in an autoproteolytic enzyme is also disclosed. Bacterial filamentation assays strongly support the interference of our compounds with the SOS response activation through inhibition of septum formation. SIGNIFICANCE: The obtained results demonstrated that phenylboronic compounds could be exploited in a hit-to-lead optimization process toward effective LexA self-cleavage inhibitors. They would sustain the rehabilitation in therapy of several dismissed antibiotics.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Compostos de Boro/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Antibacterianos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Compostos de Boro/química , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Levofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Resposta SOS em Genética/efeitos dos fármacos , Serina Endopeptidases/química , Serina Endopeptidases/genética
11.
Chem Commun (Camb) ; 56(4): 571-574, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31829349

RESUMO

A novel difluoroboron fluorophore with an electron donor-acceptor conjugated structure was synthesized with 26.5% fluorescence quantum yield, 18 035 GM two-photon absorbing cross-section, and undetectable two-photon fluorescence, resulting in 25% 1O2 quantum yield. The unique optical behavior of CNFBBN enabled one-photon fluorescence imaging and two-photon phototherapy against HeLa cancer cells, irradiated at separate wavelengths.


Assuntos
Compostos de Boro/farmacologia , Corantes Fluorescentes/farmacologia , Imagem Óptica , Fótons , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Compostos de Boro/química , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Células HeLa , Humanos , Estrutura Molecular , Fármacos Fotossensibilizantes/química , Espectrometria de Fluorescência
12.
Am J Physiol Regul Integr Comp Physiol ; 318(1): R38-R48, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596114

RESUMO

Astrocytes generate robust cytoplasmic calcium signals in response to reductions in extracellular glucose. This calcium signal, in turn, drives purinergic gliotransmission, which controls the activity of catecholaminergic (CA) neurons in the hindbrain. These CA neurons are critical to triggering glucose counter-regulatory responses (CRRs) that, ultimately, restore glucose homeostasis via endocrine and behavioral means. Although the astrocyte low-glucose sensor involvement in CRR has been accepted, it is not clear how astrocytes produce an increase in intracellular calcium in response to a decrease in glucose. Our ex vivo calcium imaging studies of hindbrain astrocytes show that the glucose type 2 transporter (GLUT2) is an essential feature of the astrocyte glucosensor mechanism. Coimmunoprecipitation assays reveal that the recombinant GLUT2 binds directly with the recombinant Gq protein subunit that activates phospholipase C (PLC). Additional calcium imaging studies suggest that GLUT2 may be connected to a PLC-endoplasmic reticular-calcium release mechanism, which is amplified by calcium-induced calcium release (CICR). Collectively, these data help outline a potential mechanism used by astrocytes to convert information regarding low-glucose levels into intracellular changes that ultimately regulate the CRR.


Assuntos
Astrócitos/fisiologia , Cálcio/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo , Rombencéfalo/citologia , Fosfolipases Tipo C/metabolismo , Anilidas/farmacologia , Animais , Antioxidantes/farmacologia , Compostos de Boro/farmacologia , Cálcio/farmacologia , Dantroleno/farmacologia , Estrenos/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Florizina/farmacologia , Pró-Fármacos , Pirrolidinonas/farmacologia , Quercetina/farmacologia , Ratos , Ratos Long-Evans , Fosfolipases Tipo C/antagonistas & inibidores
13.
Chem Commun (Camb) ; 56(7): 1078-1081, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31872834

RESUMO

A boron dipyrromethene based photosensitiser substituted with a 1,2,4,5-tetrazine moiety has been prepared of which the photoactivity can be activated upon an inverse-electron-demand Diels-Alder reaction with trans-cyclooctene derivatives. By using a biotin-conjugated trans-cyclooctene to tag the biotin-receptor-positive HeLa cells, this photosensitiser exhibits site-specific activation through cycloaddition, leading to high photocytotoxicity.


Assuntos
Compostos de Boro/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Biotina/análogos & derivados , Biotina/síntese química , Biotina/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Linhagem Celular Tumoral , Reação de Cicloadição , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/efeitos da radiação , Humanos , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
14.
Eur J Med Chem ; 185: 111858, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718946

RESUMO

Several triterpenoid acids (betulinic, oleanolic, ursolic, glycyrrhetinic) and triterpene betulin were used as starting material to synthesize BODIPY FL adducts, and these compounds were screened for their cytotoxic activity employing several human tumor cell lines. The cytotoxicity of the compounds strongly depended on the chosen spacer between the triterpenoid core and the BODIPY FL unit. Thus, 3-O-acetyl-betulinic acid derived BODIPY FL conjugate holding an ethylendiamine spacer was cytotoxic for human breast adenocarcinoma cells MCF7 but not cytotoxic for all other cell lines.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Desenho de Fármacos , Corantes Fluorescentes/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/química
15.
J Inorg Biochem ; 202: 110817, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706182

RESUMO

Cis-dichloro-oxovanadium(IV) complexes [VO(L1/L2)Cl2], where L1 is N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4ʎ4,5ʎ4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 1 and L2 is N-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4ʎ4,5ʎ4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 2) having 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene as boron-dipyrromethene (BODIPY) appended dipicolylamine bases were prepared, characterized and their photocytotoxicity studied. X-ray crystal structure of 1 showed distorted octahedral geometry with a VIVON3Cl2 core having Cl-V-Cl angle of 91.93(4)°. The complexes showed variable solution conductivity properties. They were non-electrolytes in dry DMF at 25 °C but showed 1:1 electrolytic behavior in an aqueous medium due to dissociation of one chloride ligand as evidenced from the mass spectral study. Complexes 1 and 2 showed absorption bands at 500 and 535 nm, respectively. The calf thymus DNA melting study revealed their interaction through DNA crosslinking on exposure to light which was further confirmed from the alkaline agarose gel electrophoresis using plasmid supercoiled pUC19 DNA. Complex 2 showed disruption of the mitochondrial membrane potential in the JC-1 (1,1',3,3'-tetraethyl-5,5',6,6'-tetrachloroimidacarbocyanine iodide) assay. The complexes were photocytotoxic in visible light (400-700 nm, power: 10 J cm-2) in cervical cancer HeLa and breast cancer MCF-7 cells. Complex 2 having a photoactive diiodo­boron-dipyrromethene moiety gave a singlet oxygen quantum yield (ΦΔ) value of ~0.6. It showed singlet oxygen mediated apoptotic photodynamic therapy activity with remarkably low IC50 (half maximal inhibitory concentration) value of ~0.15 µM. The cis-disposition of chlorides gave a cis-divacant 4-coordinate intermediate structure from the density functional theory (DFT) study thus mimicking the DNA crosslinking property of cisplatin.


Assuntos
Compostos de Boro , Citotoxinas , DNA , Fármacos Fotossensibilizantes , Porfobilinogênio/análogos & derivados , Vanadatos , Boro/química , Boro/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Cristalografia por Raios X , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , DNA/química , DNA/metabolismo , Células HeLa , Humanos , Células MCF-7 , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfobilinogênio/síntese química , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Vanadatos/química , Vanadatos/farmacologia
16.
Chem Commun (Camb) ; 55(90): 13518-13521, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31608902

RESUMO

A distyryl boron dipyrromethene based photosensitiser substituted with 1,2,4,5-tetrazine and alkyne moieties was prepared. Through site-specific bioorthogonal reactions with the complementary functional tags anchored on the membrane of A431 human epidermoid carcinoma cells, this versatile photosensitiser exhibited enhanced cellular uptake and photocytotoxicity. The bioorthogonal ligation was also demonstrated in tumour-bearing nude mice.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfobilinogênio/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Imagem Óptica , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfobilinogênio/síntese química , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 183: 111685, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525661

RESUMO

In this study, BODIPY compounds (2, 3, 5 and 6) bearing 3,4-bis(3-pyridin-3-ylpropoxy)benzyl, 4-(3-pyridin-3-ylpropoxy)benzyl groups were synthesized for the first time and further functionalized in a Knoevenagel condensation reaction with 3,4-bis(3-pyridin-3-ylpropoxy)benzaldehyde and 4-(3-pyridin-3-ylpropoxy)benzaldehyde. The water soluble derivatives of BODIPY compounds (3a and 6a) were synthesized by treating BODIPY compounds 3 and 6 with excess iodomethane in DMF. The photochemical properties and DNA binding modes of 3a and 6a were determined using ct-DNA by UV-Vis spectrophotometer and viscometer. DNA cleavage and topoisomerases inhibition properties were studied DNA using agarose gel electrophoresis. Their topoisomerase inhibition mechanisms were investigated at molecular level and correlations with the in vitro results were searched for using molecular docking method. In addition, cytotoxicity and phototoxicity of both compounds were performed on colorectal cancer cells (HCT-116) using MTT assay for 24 h. Annexin V-FITC/PI test was performed to determine the cell death mechanism of 6a induced by irradiation. Finally, 6a-loaded liposomes (LP6a) and PLGA nanoparticles (NP6a) were prepared and their cytotoxic and phototoxic effects were evaluated by MTT assay. The results claimed that 6a had great potential as photosensitizer agent for colorectal cancer owing to its photochemical, DNA interaction and phototoxic properties.


Assuntos
Antineoplásicos , Compostos de Boro , Neoplasias Colorretais/tratamento farmacológico , Fármacos Fotossensibilizantes , Inibidores da Topoisomerase , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Clivagem do DNA/efeitos dos fármacos , DNA Topoisomerases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia , Água
18.
Eur J Med Chem ; 182: 111646, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31521028

RESUMO

The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery.


Assuntos
Antineoplásicos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/química , Doenças Autoimunes/metabolismo , Compostos de Boro/química , Compostos de Boro/farmacologia , Bortezomib/química , Bortezomib/farmacologia , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Neoplasias Hematológicas/metabolismo , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/química
19.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509949

RESUMO

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.


Assuntos
Terapia por Captura de Nêutron de Boro , Boro/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Boro/química , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ésteres/química , Glicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Estrutura Molecular , Neoplasias/patologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Triazinas/química , Triazinas/farmacologia
20.
Macromol Rapid Commun ; 40(20): e1900291, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429995

RESUMO

Difluoroboron ß-diketonate dyes are reported to exhibit excellent photophysical properties (e.g., broad absorption and large extinction coefficients) and have the potential to act as high-performance photosensitizers in cationic photopolymerization (CP). In this study, four curcuminoid-based difluoroboron dyes (BF2 Curs) are prepared. Their ability to initiate the CP of epoxides or vinyl ethers in combination with an iodonium salt under yellow and red LEDs is investigated. Some of the BF2 Curs-based photoinitiating systems exhibit much higher efficiencies than the reported anthraquinone derivative Oil Blue N (OBN). The molecular structure of BF2 Curs is found to play a critical role in the photoinitiating efficiencies of cationic polymerization.


Assuntos
Compostos de Boro/farmacologia , Corantes/farmacologia , Curcumina/farmacologia , Luz , Fármacos Fotossensibilizantes/farmacologia , Polimerização , Compostos de Boro/química , Cátions , Corantes/química , Curcumina/química , Fotólise , Fármacos Fotossensibilizantes/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta
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