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1.
Chemosphere ; 254: 126911, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957300

RESUMO

Trivalent organoarsenicals such as methylarsenite (MAs(III)) are considerably more toxic than inorganic arsenate (As(V)) or arsenite (As(III)). In microbial communities MAs(III) exhibits significant antimicrobial activity. Although MAs(III) and other organoarsenicals contribute to the global arsenic biogeocycle, how they exert antibiotic-like properties is largely unknown. To identify possible targets of MAs(III), a genomic library of the gram-negative bacterium, Shewanella putrefaciens 200, was expressed in Escherichia coli with selection for MAs(III) resistance. One clone contained the S. putrefaciens murA gene (SpmurA), which catalyzes the first committed step in peptidoglycan biosynthesis. Overexpression of SpmurA conferred MAs(III) resistance to E. coli. Purified SpMurA was inhibited by MAs(III), phenylarsenite (PhAs(III)) or the phosphonate antibiotic fosfomycin but not by inorganic As(III). Fosfomycin inhibits MurA by binding to a conserved residue that corresponds to Cys117 in SpMurA. A C117D mutant was resistant to fosfomycin but remained sensitive to MAs(III), indicating that the two compounds have different mechanisms of action. New inhibitors of peptidoglycan biosynthesis are highly sought after as antimicrobial drugs, and organoarsenicals represent a new area for the development of novel compounds for combating the threat of antibiotic resistance.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Peptidoglicano/biossíntese , Shewanella putrefaciens/efeitos dos fármacos , Alquil e Aril Transferases/genética , Farmacorresistência Bacteriana/genética , Escherichia coli/genética , Peptidoglicano/metabolismo , Shewanella putrefaciens/genética
2.
Nat Commun ; 11(1): 3178, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576814

RESUMO

Sophisticated mechanically interlocked molecules (MIMs) with interesting structures, properties and applications have attracted great interest in the field of supramolecular chemistry. We herein report a highly efficient self-assembly of heterometallic triangular necklace 1 containing Cu and Pt metals with strong antibacterial activity. Single-crystal X-ray analysis shows that the finely arranged triangular necklace 1 has two racemic enantiomers in its solid state with intriguing packing motif. The superior antibacterial activity of necklace 1 against both standard and clinically drug-resistant pathogens implies that the presence of Cu(I) center and platinum(II) significantly enhance the bacterium-binding/damaging activity, which is mainly attributed to the highly positively charged nature, the possible synergistic effect of heterometals in the necklace, and the improved stability in culture media. This work clearly discloses the structure-property relationships that the existence of two different metal centers not only facilitates successful construction of heterometallic triangular necklace but also endows it with superior nuclease properties and antibacterial activities.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Bactérias/efeitos dos fármacos , Cobre/química , Cristalografia por Raios X , Clivagem do DNA/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Platina/química , Estereoisomerismo
3.
PLoS One ; 15(4): e0230966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32243463

RESUMO

Various types of stem cells and non-stem cells have been shown to differentiate or transdifferentiate into cardiomyocytes by way of co-culture with appropriate inducer cells. However, there is a limited demonstration of a co-culture induction system utilizing stem cell-derived cardiomyocytes as a stimulatory source for cardiac reprogramming (of stem cells or otherwise). In this study, we utilized an inductive co-culture method to show that previously differentiated induced pluripotent stem (iPS) cell-derived cardiomyocytes (iCMs), when co-cultivated with iPS cells, constituted a sufficient stimulatory system to induce cardiac differentiation. To enable tracking of both cell populations, we utilized GFP-labeled iPS cells and non-labeled iCMs pre-differentiated using inhibitors of GSK and Wnt signaling. Successful differentiation was assessed by the exhibition of spontaneous self-contractions, structural organization of α-actinin labeled sarcomeres, and expression of cardiac specific markers cTnT and α-actinin. We found that iCM-iPS cell-cell contact was essential for inductive differentiation, and this required overlaying already adherent iPS cells with iCMs. Importantly, this process was achieved without the exogenous addition of pathway inhibitors and morphogens, suggesting that 'older' iCMs serve as an adequate stimulatory source capable of recapitulating the necessary culture environment for cardiac differentiation.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Actinina/metabolismo , Benzotiazóis/farmacologia , Biomarcadores/metabolismo , Comunicação Celular , Diferenciação Celular , Linhagem Celular , Transdiferenciação Celular , Reprogramação Celular , Técnicas de Reprogramação Celular/métodos , Técnicas de Cocultura/métodos , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Compostos Organometálicos/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
4.
Arch Biochem Biophys ; 687: 108383, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32335048

RESUMO

Intracellular carbon monoxide (CO) is a gaseous signaling molecule and is generated enzymatically by heme oxygenases upon degradation of heme to billiverdin. Target structures for intracellular produced CO are heme proteins including cytochrome c oxidase of the respiratory chain, cytochrome P450-dependent monooxygenases, or myoglobin. For studies on CO signaling, CO-releasing molecules (CORMs) of different structure are available. Here, three frequently used CORMs (CORM-2, CORM-3 and CORM-401) were studied for their properties to provide CO in biological test systems and address susceptible heme proteins. CO release was investigated in the myoglobin binding assay and found to be rapid (<5 min) with CORM-2- and CORM-3, whereas CORM-401 continuously provided CO (>50 min). Storage stability of CORM stock solutions was also assessed with the myoglobin assay. Only CORM-401 stock solutions were stable over a period of 7 days. Incubation of CORMs with recombinant cytochrome P450 led to an inhibition of enzyme activity. However, only CORM-3 and CORM-401 proved to be suitable in this test system because controls with the inactivated CORM-2 (iCORM-2) also led to a loss of enzyme activity. The impact of CORMs on the respiratory chain was investigated with high resolution respirometry and extracellular flux technology. In the first approach interferences of CORM-2 and CORM-3 with oxygen measurement occurred, since a rapid depletion of oxygen was detected in the medium even when no cells were present. However, CORM-401 did not interfere with oxygen measurement and the expected inhibition of cellular respiration was observed. CORM-2 was not suitable for use in oxygen measurements with the extracellular flux technology and CORM-3 application did not show any effect in this system. However, CO-dependent inhibition of cellular respiration was observed with CORM-401. Based on the present experiments it is concluded, that CORM-401 produced most reliable CO-specific results for the modulation of typical CO targets. For studies on CO-dependent biological effects on intracellular heme groups, CORM-2 and CORM-3 were less suitable. Depending on the experimental setting, data achieved with these compounds should be evaluated with caution.


Assuntos
Monóxido de Carbono/metabolismo , Glicinas N-Substituídas/farmacologia , Compostos Organometálicos/farmacologia , Animais , Respiração Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/antagonistas & inibidores , Estabilidade de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Glicinas N-Substituídas/química , Compostos Organometálicos/química
5.
Res Vet Sci ; 130: 153-160, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193002

RESUMO

The aim of this study was to investigate the antihypertensive properties of cis-[Ru(bpy)2ImN(NO)]3+ (FOR0811) in normotensive and in Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Vasorelaxant effects were analyzed by performing concentration response curve to FOR0811 in rat aortic rings in the absence or presence of 1H-[1,2,4]-oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ), L-cysteine or hydroxocobalamin. Normotensive and L-NAME-hypertensive rats were treated with FOR0811 and the effects in blood pressure and heart rate variability in the frequency domain (HRV) were followed. FOR0811 induced relaxation in rat aortic rings. Neither endothelium removal nor L-cysteine altered the FOR0811 effects. However, the incubation with ODQ and hydroxocobalamin completely blunted FOR0811 effects. FOR0811 administered intravenously by bolus infusion (0.01-1 mg/bolus) or chronically by using subcutaneous implanted osmotic pumps significantly reduced the mean arterial blood pressure. The effect was long lasting and did not induce reflex tachycardia. FOR0811 prevented both LF and VLF increases in L-NAME hypertensive rats and has antihypertensive properties. This new ruthenium complex compound might be a promising nitric oxide donor to treat cardiovascular diseases.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Ratos , Ratos Wistar
6.
Acta Cir Bras ; 34(12): e201901201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32022101

RESUMO

PURPOSE: To evaluate the effect of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor, able to modulate the histological changes caused by the NASID (meloxicam). METHODS: Wistar rats were assigned into three groups (n=6 rats/group): Sham group (saline solution), NSAID group (meloxicam - 15 mg/kg) and Rut-bpy group (100 mg/kg of Rut-bpy associated with 15mg/kg of meloxicam). At the end of experiments, kidneys were removed for histological study, fractal dimension and lacunarity in all animals. RESULTS: At the histological examination, all animals (six animals - 100 %) in the NSAID group had membrane thickening and other changes (necrosis, acute tubular congestion and vascular congestion); on the other hand, only one animal (16.6 %) of the Rut-bpy group had congestion. The fractal dimension and lacunarity were greater in the control and Rut-bpy group than in NSAIDs group (p<0.05). CONCLUSION: Rut-bpy may prevent renal histological changes in rats caused by meloxicam.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Meloxicam/efeitos adversos , Doadores de Óxido Nítrico/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , 2,2'-Dipiridil/análogos & derivados , Animais , Fractais , Nefropatias/patologia , Masculino , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes
7.
J Photochem Photobiol B ; 204: 111811, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32028187

RESUMO

The development of multidrug resistance is often associated with the over-expression of P-glycoprotein (P-gp). This protein prevents drug accumulation and extrudes them out of the cell before they reach the intended target. The aim of this study was to develop an in vitro MCF-7 cell line with increased expression of P-gp and test the phototoxicity of a novel photoactivated zinc phthalocyanine tetrasulfonic acid (ZnPcS4) on these cells. The over-expressed P-gp MCF-7 cells (MCF-7/DOX) were developed from wildtype (WT) MCF-7 cells by a stepwise continuous exposure of the WT cells to different concentrations of Doxorubicin (DOX) (0.1 - 1 µM) over a period of 4 months. The P-gp expression was measured using flow cytometry, immunofluorescence and enzyme immunoassay. To verify whether zinc phthalocyanine-mediated photodynamic therapy (ZnPcS4 - PDT) is effective in MCF-7/DOX, we studied the subcellular localization, phototoxicity and nuclear damage. The flow cytometry result showed two distinct peaks of P-gp positive and negative expression in MCF-7/DOX cell population, which correlates with the ELISA-based assay (p˂0.001). The ME16C (Normal breast cells) was used as control. The localization studies showed that ZnPcS4 have greater affinity for lysosome than mitochondria. Phototoxicity results indicated that photoactivated zinc phthalocyanine decreased the cell proliferation and viability as the drug and laser light dosages increased to 16 µM and 20 J/cm2 respectively. PDT-induced cytotoxicity using lactose dehydrogenase (LDH) enzyme leakage as measure did not increase likewise. The ZnPcS4-induced PDT was less effective for MCF-7/DOX cells which could be attributed to decreased retention of ZnPcS4 in major cellular organelles due to the presence of increased drug efflux P-gp. The current findings suggest that, increased P-gp expression, a characteristic of multidrug resistance together with other related intrinsic mechanisms might contribute to render MCF-7/DOX cells less sensitive to ZnPcS4-induced phototoxicity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Lasers Semicondutores , Compostos Organometálicos/farmacologia , Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Feminino , Humanos , Indóis/química , Células MCF-7 , Compostos Organometálicos/química , Fotoquimioterapia , Rodamina 123/química , Rodamina 123/metabolismo
8.
J Exp Clin Cancer Res ; 39(1): 40, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087737

RESUMO

BACKGROUND: Osteosarcoma (OS) is an aggressive malignant neoplasm that still suffers from poor prognosis in the case of distal metastases or occurrence of multi-drug resistance. It is therefore crucial to find novel therapeutic options able to go beyond these limitations and improve patients' survival. The objective of this study is to exploit the intrinsic properties of mesenchymal stromal cells (MSCs) to migrate and infiltrate the tumor stroma to specifically deliver therapeutic agents directly to cancer cells. In particular, we aimed to test the efficacy of the photoactivation of MSCs loaded with nanoparticles in vitro and in a murine in vivo ectopic osteosarcoma model. METHODS: AlPcS4@FNPs were produced by adding tetra-sulfonated aluminum phthalocyanine (AlPcS4) to an aqueous solution of positively charged poly-methyl methacrylate core-shell fluorescent nanoparticles (FNPs). The photodynamic therapy (PDT) effect is achieved by activation of the photosensitizer AlPcS4 in the near-infrared light with an LED source. Human MSCs were isolated from the bone marrow of five donors to account for inter-patients variability and used in this study after being evaluated for their clonogenicity, multipotency and immunophenotypic profile. MSC lines were then tested for the ability to internalize and retain the nanoparticles, along with their migratory properties in vitro. Photoactivation effect was evaluated both in a monolayer (2D) co-culture of AlPcS4@FNPs loaded MSCs with human OS cells (SaOS-2) and in tridimensional (3D) multicellular spheroids (AlPcS4@FNPs loaded MSCs with human OS cells, MG-63). Cell death was assessed by AnnexinV/PI and Live&Dead CalceinAM/EthD staining in 2D, while in the 3D co-culture, the cell killing effect was measured through ATP content, CalceinAM/EthD staining and TEM imaging. We also evaluated the effectiveness of AlPcS4@FNPs loaded MSCs as delivery systems and the ability of the photodynamic treatment to kill cancer cells in a subcutaneous mouse model of OS by bioluminescence imaging (BLI) and histology. RESULTS: MSCs internalized AlPcS4@FNPs without losing or altering their motility and viability in vitro. Photoactivation of AlPcS4@FNPs loaded MSCs induced high level of OS cells death in the 2D co-culture. Similarly, in the 3D co-culture (MSCs:OS ratios 1:1 or 1:3), a substantial decrease of both MSCs and OS cells viability was observed. Notably, when increasing the MSCs:OS ratio to 1:7, photoactivation still caused more than 40% cells death. When tested in an in vivo ectopic OS model, AlPcS4@FNPs loaded MSCs were able to decrease OS growth by 68% after two cycles of photoactivation. CONCLUSIONS: Our findings demonstrate that MSCs can deliver functional photosensitizer-decorated nanoparticles in vitro and in vivo and inhibit OS tumor growth. MSCs may be an effective platform for the targeted delivery of therapeutic nanodrugs in a clinical scenario, alone or in combination with other osteosarcoma treatment modalities.


Assuntos
Neoplasias Ósseas/terapia , Indóis/administração & dosagem , Células-Tronco Mesenquimais/citologia , Compostos Organometálicos/administração & dosagem , Osteossarcoma/terapia , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Indóis/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/química , Camundongos , Nanopartículas , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Molecules ; 25(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936104

RESUMO

Metallation of biomacromolecular species forms the basis for the anticancer activity of many metallodrugs. A major limitation of these compounds is that their reactivity is indiscriminate and can, in principle, occur in healthy tissue as well as cancerous tissue, potentially leading to side effects in vivo. Here we present pH-dependent intramolecular coordination of an arene-tethered sulfonamide functionality in organometallic ruthenium(II) ethylenediamine complexes as a route to controlling the coordination environment about the central metal atom. Through variation of the sulfonamide R group and the length of the tether linking it to the arene ligand the acidity of the sulfonamide NH group, and hence the pH-region over which regulation of metal coordination occurs, can be modulated. Intramolecular sulfonamide ligation controlled the reactivity of complex 4 within the physiologically relevant pH-region, rendering it more reactive towards 5'-GMP in mildly acidic pH-conditions typical of tumour tissue compared to the mildly alkaline pH-conditions typical of healthy tissue. However, the activation of 4 by ring-opening of the chelate was found to be a slow process relative to the timescale of typical cell culture assays and members of this series of complexes were found not to be cytotoxic towards the HT-29 cell line. These complexes provide the basis for the development of analogues of increased potency where intramolecular sulfonamide ligation regulates reactivity and therefore cytotoxicity in a pH-dependent, and potentially, tissue-dependent manner.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Diaminas/química , Compostos Organometálicos/farmacologia , Rutênio/química , Sulfonamidas/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Diaminas/farmacologia , Etilenodiaminas/química , Etilenodiaminas/farmacologia , Guanosina Monofosfato/metabolismo , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Cinética , Ligantes , Modelos Moleculares , Compostos Organometálicos/química , Rutênio/farmacologia , Sulfonamidas/farmacologia
11.
Chemistry ; 26(8): 1789-1799, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31605633

RESUMO

The synthesis of ruthenium(II) phthalocyanines (RuPcs) endowed with one carbohydrate unit-that is, glucose, galactose and mannose-and a dimethylsulfoxide (DMSO) ligand at the two axial coordination sites, respectively, is described. Two series of compounds, one unsubstituted at the periphery, and the other one bearing eight PEG chains at the isoindole meta-positions, have been prepared. The presence of the axial DMSO unit significantly increases the phthalocyanine singlet oxygen quantum yields, related to other comparable RuPcs. The compounds have been evaluated for PDT treatment in bladder cancer cells. In vitro studies have revealed high phototoxicity for RuPcs unsubstituted at their periphery. The phototoxicity of PEG-substituted RuPcs has been considerably improved by repeated light irradiation. The choice of the axial carbohydrate introduced little differences in the cellular uptake for both series of photosensitizers, but the phototoxic effects were considerably higher for compounds bearing mannose units.


Assuntos
Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Oxigênio Singlete/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Luz , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Espectrofotometria , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo
12.
J Enzyme Inhib Med Chem ; 35(1): 59-64, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663383

RESUMO

A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against ß-class CAs, herein we report an inhibition study with this class of compounds against ß-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for ß-class over human isozymes, making them interesting leads for the development of new anti-infectives.


Assuntos
Amidas/farmacologia , Anti-Infecciosos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organometálicos/farmacologia , Ácidos Fosfóricos/farmacologia , Amidas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Fungos/enzimologia , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Ácidos Fosfóricos/química , Fósforo/química , Fósforo/farmacologia , Relação Estrutura-Atividade , Zinco/química , Zinco/farmacologia
13.
Dalton Trans ; 49(5): 1403-1415, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31851200

RESUMO

The synthesis, characterization and biological activity of six bioorganometallic conjugates of ciprofloxacin with ferrocenyl, ruthenocenyl and cymantrenyl entities are described. Their antimicrobial activities were investigated against Gram-positive bacteria, Gram-negative bacteria and bloodstream forms of Trypanosoma brucei. Furthermore, the morphological changes of bacterial cells upon treatment with the conjugates were examined by scanning electron microscopy. In addition, the cytotoxicity of the conjugates against tumor and normal mammalian cells was also investigated. The results showed that conjugation of an organometallic moiety can significantly enhance the antimicrobial activity of the antibiotic ciprofloxacin drug. It was found that N-alkyl cymantrenyl and ruthenocenyl ciprofloxacin conjugates were the most effective derivatives although other conjugates also showed significant antimicrobial activity. The increase in the antimicrobial activity was most likely due to two independent mechanisms of action. The first mechanism is due to the bacterial topoisomerase inhibitory activity of ciprofloxacin while the second mechanism can be attributed to the generation of reactive oxygen species caused by the organometallic moiety. The presence of two modes of action enables the conjugates to kill bacteria in their stationary growth phase and to overcome the drug resistance of S. aureus strains. In addition, the conjugates showed promising selectivity toward bacterial and parasitic cells over mammalian cells.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Ciprofloxacino/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciprofloxacino/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade
14.
Anticancer Drugs ; 31(1): 55-59, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609767

RESUMO

Heterocyclic organobismuth compounds, such as N-tert-butyl-bi-chlorodibenzo[c,f][1,5]azabismocine (compound 1) and bi-chlorodibenzo[c,f ][1,5]thiabismocine (compound 3), exert potent antiproliferative activities in vitro in human cancer cell lines. We showed that compound 3 induced both apoptotic and nonapoptotic cell death via reactive oxygen species production and mitotic arrest in a dose-dependent manner. The mechanisms underlying the dose-dependent effect of these organobismuth compounds were not clear. In the present study, we examined the dose-dependent mechanism underlying cell death induced by compound 1 in a human pancreatic cancer cell line, SUIT-2, and a human colorectal cancer cell line, DLD-1. Compound 1 inhibited cell growth in a dose-dependent manner and induced cell death. Treatment with the pan-caspase inhibitor zVAD-fmk reduced cell death induced by compound 1, whereas the inhibitory effect of zVAD-fmk was limited. Moreover, compound 1 significantly induced lipid peroxidation with concomitant induction of caspase-independent cell death. Our results suggested that eight-membered ring organobismuth compounds induce nonapoptotic cell death via lipid peroxidation.


Assuntos
Antineoplásicos/farmacologia , Bismuto/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Isoquinolinas/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Bismuto/química , Inibidores de Caspase/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Isoquinolinas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Compostos Organometálicos/química , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia
15.
Dalton Trans ; 48(48): 17925-17935, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31793567

RESUMO

Three novel copper(ii) complexes, Cu(L1)2 (1), Cu(L2)2·2DMF (2), and Cu(L3)2·2DMF (3), were synthesized using three aroylhydrazone ligands, (E)-2-hydroxy-N'-(1-(pyrazin-2-yl)ethylidene)benzohydrazide (HL1), (E)-3-hydroxy-N'-(1-(pyrazin-2-yl)ethylidene)benzohydrazide (HL2) and (E)-4-hydroxy-N'-(1-(pyrazin-2-yl)ethylidene)benzohydrazide (HL3). The complexes were characterized by elemental analysis, infrared (IR), and Ultraviolet-visible light (UV-vis) spectroscopy. The X-ray crystal structures of the complexes all possess a distorted octahedral coordination geometry. Both an absorption spectral titration and a competitive binding assay (ethidium bromide, 4',6-diamidino-2-phenylindole (DAPI), and methyl green) revealed that complexes 2 and 3 bind readily to calf thymus DNA (ctDNA) through intercalative and minor groove binding modes. Complexes 2 and 3 also exhibited oxidative cleavage of supercoiled plasmid DNA (pUC19) in the presence of ascorbic acid as an activator. Cytotoxicity studies showed that complexes 2 and 3 possessed high cytotoxicities toward the HeLa human cervical cancer cell line, but weak toxicities toward the L929 normal mouse fibroblast cell line. We therefore have reason to believe that complexes 2 and 3 both show potential as promising anticancer candidate drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cobre/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Clivagem do DNA , Humanos , Ligantes , Camundongos , Modelos Moleculares , Estrutura Molecular
16.
J Immunother Cancer ; 7(1): 350, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842994

RESUMO

BACKGROUND: Anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT). METHODS: Cell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11c+CD86+, CD11c+CD40+) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model. RESULTS: We determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm2 (λex 615-635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo. CONCLUSIONS: Altogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy.


Assuntos
Glucosamina/análogos & derivados , Indóis/farmacologia , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Biomarcadores , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Imunofluorescência , Glucosamina/farmacologia , Camundongos , Fagocitose/efeitos dos fármacos
17.
Oxid Med Cell Longev ; 2019: 2510936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772702

RESUMO

Tellurium is a rare element that has been regarded as a toxic, nonessential element, and its biological role is not clearly established. In addition, the biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and prooxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties. In addition, DPDT may exert its effects through different pathways, including distinct ones to those responsible for chemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion, structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to present recent advances in our understanding of the biological effects, therapeutic potential, and safety of DPDT treatment. Moreover, original results demonstrating the cytotoxic effects of DPDT in different mammalian cell lines and systems biology analysis are included, and emerging approaches for possible future applications are inferred.


Assuntos
Antioxidantes/uso terapêutico , Derivados de Benzeno/uso terapêutico , Compostos Organometálicos/uso terapêutico , Telúrio/química , Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Humanos , Compostos Organometálicos/farmacologia , Oxirredução
18.
Molecules ; 24(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779066

RESUMO

Herein, we report the synthesis, characterisation, X-ray crystallography, and oxidative DNA binding interactions of the copper artificial metallo-nuclease [Cu(DPQ)2(NO3)](NO3), where DPQ = dipyrido[3,2-f:2',3'-h]quinoxaline. The cation [Cu(DPQ)2]2+ (Cu-DPQ), is a high-affinity binder of duplex DNA and presents an intercalative profile in topoisomerase unwinding and viscosity experiments. Artificial metallo-nuclease activity occurs in the absence of exogenous reductant but is greatly enhanced by the presence of the reductant Na-L-ascorbate. Mechanistically, oxidative DNA damage occurs in the minor groove, is mediated aerobically by the Cu(I) complex and is dependent on both superoxide and hydroxyl radical generation. To corroborate cleavage at the minor groove, DNA oxidation of a cytosine-guanine (5'-CCGG-3')-rich oligomer was examined in tandem with a 5-methylcytosine (5'-C5mCGG-3') derivative where 5mC served to sterically block the major groove and direct damage to the minor groove. Overall, both the DNA binding affinity and cleavage mechanism of Cu-DPQ depart from Sigman's reagent [Cu(1,10-phenanthroline)2]2+; however, both complexes are potent oxidants of the minor groove.


Assuntos
Cobre/farmacologia , Clivagem do DNA/efeitos dos fármacos , DNA/metabolismo , Desoxirribonucleases/metabolismo , Compostos Organometálicos/farmacologia , Quinoxalinas/farmacologia , Superóxidos/metabolismo , Cristalografia por Raios X/métodos , Citosina/metabolismo , Dano ao DNA/efeitos dos fármacos , Guanina/metabolismo , Radical Hidroxila/metabolismo , Substâncias Intercalantes/farmacologia , Oxirredução/efeitos dos fármacos
19.
Int J Nanomedicine ; 14: 6799-6812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692522

RESUMO

Background: Photodynamic therapy (PDT), a clinical anticancer therapeutic modality, has a long history in clinical cancer treatments since the 1970s. However, PDT has not been widely used largely because of metabolic problems and off-target phototoxicities of the current clinical photosensitizers. Purpose: The objective of the study is to develop a high-efficiency and high-specificity carrier to precisely deliver photosensitizers to tumor sites, aiming at addressing metabolic problems, as well as the systemic damages current clinical photosensitizers are known to cause. Methods: We synthesized a polydopamine (PDA)-based carrier with the modification of folic acid (FA), which is to target the overexpressed folate receptors on tumor surfaces. We used this carrier to load a cationic phthalocyanine-type photosensitizer (Pc) and generated a PDA-FA-Pc nanomedicine. We determined the antitumor effects and the specificity to tumor cell lines in vitro. In addition, we established human cancer-xenografted mice models to evaluate the tumor-targeting property and anticancer efficacies in vivo. Results: Our PDA-FA-Pc nanomedicine demonstrated a high stability in normal physiological conditions, however, could specifically release photosensitizers in acidic conditions, eg, tumor microenvironment and lysosomes in cancer cells. Additionally, PDA-FA-Pc nanomedicine demonstrated a much higher cellular uptake and phototoxicity in cancer cell lines than in healthy cell lines. Moreover, the in vivo imaging data indicated excellent tumor-targeting properties of PDA-FA-Pc nanomedicine in human cancer-xenografted mice. Lastly, PDA-FA-Pc nanomedicine was found to significantly suppress tumor growth within two human cancer-xenografted mice models. Conclusion: Our current study not only demonstrates PDA-FA-Pc nanomedicine as a highly potent and specific anticancer agent, but also suggests a strategy to address the metabolic and specificity problems of clinical photosensitizers.


Assuntos
Ácido Fólico/farmacologia , Indóis/farmacologia , Nanopartículas/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Polímeros/farmacologia , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Estabilidade de Medicamentos , Feminino , Ácido Fólico/química , Células HeLa , Humanos , Indóis/química , Células MCF-7 , Camundongos , Nanomedicina , Nanopartículas/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Polímeros/química , Ensaios Antitumorais Modelo de Xenoenxerto
20.
BMC Med Imaging ; 19(1): 83, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653206

RESUMO

BACKGROUND: Magnetic resonance arthrography (MRA) requires intra-articular injection of gadolinium-based diluted paramagnetic contrast material. To our knowledge, gadobenate dimeglumine (Gd-BOPTA) has never been used for intra-articular applications. Our aim was to test in vitro different concentrations of Gd-BOPTA to be potentially used to perform MRA. METHODS: Gd-BOPTA was diluted in saline (NaCl 0.9%) to achieve different concentrations (4 mmol/l; 2 mmol/l; 1 mmol/l; 0.67 mmol/l; 0.5 mmol/l). Six sets of five sterile pipes were prepared with 5 ml of each solution, five sets added with 0.5 ml of fresh synovial fluid. Two separate pipes were prepared with 5 ml of gadopentetate dimeglumine (Gd-DTPA) at 2 mmol/l, one pipe added with 0.5 ml of synovial fluid. Pipes were imaged using a T1-weighted sequence at 1.5 T. For each pipe, signal intensity (SI) in arbitrary units (au) was measured. RESULTS: SI reproducibility range was 86-99%. Mean Gd-BOPTA SI in pipes containing synovial fluid increased from 1236 ± 8au (0.5 mmol/l) up to 1610 ± 44au (1 mmol/l) and down to 1405 ± 33au (4 mmol/l). Mean Gd-BOPTA SI in pipes without synovial fluid increased from 1184 ± 29au (0.5 mmol/l) up to 1530 ± 38au (1 mmol/l), and down to 1347 ± 39au (4 mmol/l). SI of pipes without synovial fluid was lower than that of pipes with synovial fluid for both Gd-BOPTA and Gd-DTPA (P ≤ 0.002). Regarding pipes with synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1246 ± 27au. Compared with Gd-BOPTA, SI was not different at 0.5 mmol/l (- 0.2%, P = 0.587) while it was higher (P < 0.001) at all other concentrations (range + 13.3%[4 mmol/l] - + 28.3%[1 mmol/l]). Regarding pipes without synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1275 ± 56au. Compared with Gd-BOPTA, SI was lower at 0.5 mmol/l (- 6.8%,P < 0.001), while it was higher (P < 0.001) at all other concentrations (range + 6.1%[4 mmol/l] - + 19.6% [1 mmol/l]). CONCLUSIONS: In vitro, Gd-BOPTA at 1 mmol/ had a + 28% SI increase in comparison to Gd-DTPA 2 mmol/l. SI similar to Gd-DTPA can be obtained using one fourth concentration of Gd-BOPTA.


Assuntos
Artrografia/métodos , Meios de Contraste/administração & dosagem , Meglumina/análogos & derivados , Compostos Organometálicos/administração & dosagem , Líquido Sinovial/diagnóstico por imagem , Idoso , Meios de Contraste/farmacologia , Feminino , Humanos , Técnicas In Vitro , Injeções Intra-Articulares , Imagem por Ressonância Magnética/métodos , Masculino , Meglumina/administração & dosagem , Meglumina/farmacologia , Pessoa de Meia-Idade , Compostos Organometálicos/farmacologia , Reprodutibilidade dos Testes
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