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1.
Toxicol Lett ; 318: 22-29, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634547

RESUMO

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R3SnX (R is butyl or phenyl, X is isothiocyanate), which are considered RXR ligands, were investigated in the human MDA-MB-231 breast cancer cell line. Studies were evaluated in the presence and absence of all-trans retinoic acid (ATRA), a natural RAR ligand. Vimentin represents the major protein associated with epithelial-mesenchymal transition (EMT), an essential process when the primary tumour transforms into a malignant one. mRNA and proteomic data obtained in this study, based on the PDQuest software protein evaluation and further quantification of proteins by iTRAQ analysis, suggest that vimentin was significantly reduced in the combination of RAR ligand and RXR ligand treatment. Both tested triorganotin compounds showed similarly reduced expression of vimentin, but tributyltin isothiocyanate (TBT-ITC) proved to be more effective than triphenyltin isothiocyanate (TPT-ITC). Furthermore, the effect of natural (9cRA) and synthetic RXR ligands, both chloride and isothiocyanate derivatives, on vimentin expression was compared.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteômica/métodos , Receptores X Retinoide/agonistas , Compostos de Trialquitina/farmacologia , Vimentina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Eletroforese em Gel Bidimensional , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Compostos Orgânicos de Estanho/farmacologia , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Tretinoína/farmacologia
2.
Eur J Med Chem ; 181: 111544, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374420

RESUMO

There is a growing interest in the cancer cell growth inhibitory effects of organotin (IV) compounds and, accordingly, a new series of dimethyl-, di-(n-butyl)-, diphenyl- and chloro-phenyl tin(IV) complexes with a Schiff base core were prepared. Their binding to DNA was assessed by UV thermal denaturation showing no interaction and by UV-vis titration exhibiting moderate interaction by intercalation. Complexes having n-butyl substituents were more potent and cytotoxic against human leukemia, breast and cervical cancer cell lines than other organotin(IV) complexes tested. Unfortunately, some of these compounds showed similar cytotoxicity in a non-cancerous cell line. We may conclude that cytotoxic activity was dependent on the nature (lipophilicity and size, according to the structure-activity relationship studies) and substitution pattern on the different structures. These results may aid in the rational design of metallodrugs, expanding the scope of organotin complexes in formulating new metal based drugs with dibutyl moieties.


Assuntos
Antineoplásicos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HeLa , Humanos , Células MCF-7 , Estrutura Molecular , Compostos Orgânicos de Estanho/síntese química , Compostos Orgânicos de Estanho/química , Relação Estrutura-Atividade
3.
Plant Dis ; 103(9): 2271-2276, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31287371

RESUMO

Sensitivity monitoring of Venturia effusa, cause of pecan scab, has revealed insensitivity to fentin hydroxide and tebuconazole, but recent research indicates that the insensitivity to fentin hydroxide is not stable. A study was undertaken to determine if a fitness cost may be responsible for this instability. In this study, experiments were conducted to evaluate fitness components and phenotypic stability of insensitivity of V. effusa to fentin hydroxide and tebuconazole. Conidial production, conidial germination, microcolony growth, sensitivity to osmotic stress, and sensitivity to oxidative stress in the absence of fungicide were compared for isolates with differing sensitivities to both fungicides. Percent conidial germination decreased linearly with increasing fentin hydroxide insensitivity, and microcolony growth on 1.0 mM H2O2 decreased linearly with increasing tebuconazole insensitivity. Stability of resistance was assessed on concentrations of 1.0, 3.0, and 10 µg/ml of both fungicides prior to and after five transfers on non-fungicide-amended medium. Tebuconazole insensitivity was stable after transfers, but fentin hydroxide insensitivity on 1.0 and 3.0 µg/ml decreased significantly after transfers, indicating instability. Here we provide evidence that in V. effusa tebuconazole insensitivity is stable and fentin hydroxide insensitivity is not. These results suggest that fentin-hydroxide-resistant V. effusa isolates have reduced conidial viability compared with sensitive isolates, which may allow the population to regain sensitivity in the absence of this frequently used fungicide.


Assuntos
Ascomicetos , Farmacorresistência Fúngica , Compostos Orgânicos de Estanho , Triazóis , Ascomicetos/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Triazóis/farmacologia
4.
Int J Mol Sci ; 20(5)2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30857277

RESUMO

The cytotoxicity of two recently synthesized triorganotin isothiocyanate derivatives, nuclear retinoid X receptor ligands, was tested and compared in estrogen-receptor-positive MCF 7 and -negative MDA-MB-231 human breast carcinoma cell lines. A 48 h MTT assay indicated that tributyltin isothiocyanate (TBT-ITC) is more cytotoxic than triphenyltin isothiocyanate (TPT-ITC) in MCF 7 cells, and the same trend was observed in the MDA-MB-231 cell line. A comet assay revealed the presence of both crosslinks and increasing DNA damage levels after the 17 h treatment with both derivatives. Differences in cytotoxicity of TBT-ITC and TPT-ITC detected by FDA staining correspond to the MTT data, communicating more pronounced effects in MCF 7 than in the MDA-MB-231 cell line. Both derivatives were found to cause apoptosis, as shown by the mitochondrial membrane potential (MMP) depolarization and caspase-3/7 activation. The onset of caspase activation correlated with MMP dissipation and the total cytotoxicity more than with the amount of active caspases. In conclusion, our data suggest that the DNA damage induced by TBT-ITC and TPT-ITC treatment could underlie their cytotoxicity in the cell lines studied.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Receptores X Retinoide/metabolismo , Compostos de Trialquitina/farmacologia , Antineoplásicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Isotiocianatos/química , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Orgânicos de Estanho/química , Compostos de Trialquitina/química
5.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781445

RESUMO

Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph2SnCl2 or Me2SnCl2 with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R2Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me2Sn(S2MoVa), Me2Sn(S4MoVa) and Me2Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C2NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.


Assuntos
Benzaldeídos/síntese química , Benzaldeídos/farmacologia , Simulação por Computador , Compostos Orgânicos de Estanho/síntese química , Compostos Orgânicos de Estanho/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Benzaldeídos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , DNA/metabolismo , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Compostos Orgânicos de Estanho/química , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/química
6.
J Biol Inorg Chem ; 24(2): 223-234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30759278

RESUMO

Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206-211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480-488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776-791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15 min with stable adhesion to the cell membrane. After only 2 h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.


Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Compostos Orgânicos de Estanho/farmacologia , Dióxido de Silício/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/patologia , Compostos Orgânicos de Estanho/química , Tamanho da Partícula , Fenótipo , Dióxido de Silício/química , Propriedades de Superfície
7.
Gen Physiol Biophys ; 38(2): 135-144, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806631

RESUMO

Trialkyltins and triaryltins function as nuclear retinoid X receptors (RXR) agonists due to their affinity to the ligand-binding domain of RXR subtypes and function as transcriptional activators. We present the data on combined effects of all-trans retinoic acid (ATRA), retinoic acid receptor (RAR) ligand and tributyltin chloride or triphenyltin chloride (RXR ligands) on protein pattern in MDA-MB-231 cells. Proteomic strategies based on bottom-up method were applied in this study. The total cell proteins were extracted, separated on 2D SDS-PAGE and their characterization was achieved by MALDI-TOF/TOF MS/MS. By employing PDQuest™ software, we identified more than 30 proteins differently affected by the above compounds. For further studies, we selected specific proteins associated either with metabolic pathway (glyceraldehyde-3-phosphate dehydrogenase) or to cellular processes as apoptosis, regulation of gene transcription or epithelial-mesenchymal transition (annexin 5, nucleoside diphosphate kinase B and vimentin). We have found that treatment of MDA-MB-231 cells with triorganotins reduced the expression of studied proteins. Moreover, the treatment of MDA-MB-231 cells with triorganotin compounds together with ATRA resulted in an additional reduction of annexin 5, vimentin and nucleoside diphosphate kinase B. These results demonstrate that RXR/RAR heterodimer may act under this experimental design as permissive heterodimer allowing activation of RXR by triorganotins.


Assuntos
Neoplasias da Mama , Compostos Orgânicos de Estanho , Proteômica , Tretinoína , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Células MCF-7 , Compostos Orgânicos de Estanho/farmacologia , Espectrometria de Massas em Tandem , Tretinoína/farmacologia
8.
Toxicol In Vitro ; 55: 11-14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30439410

RESUMO

Triphenyltin (TPT) is an organotin compound causing environmental hazard to many wild creatures. Our previous findings show that TPT increases of the frequency of spontaneous glycinergic inhibitory postsynaptic currents (sIPSCs) in rat spinal neurons without changing the amplitude and 1/e decay time. In our study, the effects of 2-aminoethoxydiphenyl borate (2-APB), dantrolene sodium, and thapsigargin on sIPSC frequency were examined to reveal the contribution of intra-axonal Ca2+ mobilization by adding TPT. 2-APB considerably attenuated the TPT-induced facilitation of sIPSC frequency while dantrolene almost completely masked the TPT effects, suggesting that the TPT-induced synaptic facilitation results from the activation of both IP3 and ryanodine receptors on endoplasmic reticulum (ER) membrane, though inositol triphosphate (IP3) receptor is less sensitive to TPT. Thapsigargin itself significantly increased the sIPSC frequency without affecting the current amplitude and decay time. Successive addition of TPT could not further increase the sIPSC frequency in the presence of thapsigargin, indicating that thapsigargin completely masked the facilitatory action of TPT. Results suggest that TPT activates the IP3 and ryanodine receptors while TPT inhibits the Ca2+-pump of ER membranes, resulting in the elevation of intra-axonal Ca2+ levels, leading to the increase of spontaneous glycine release from synaptic vesicles.


Assuntos
Cálcio/fisiologia , Glicina/fisiologia , Neurônios/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Animais , Compostos de Boro/farmacologia , Dantroleno/farmacologia , Feminino , Masculino , Neurônios/fisiologia , Ratos Wistar , Medula Espinal/citologia , Transmissão Sináptica/efeitos dos fármacos , Tapsigargina/farmacologia
9.
Inorg Chem ; 58(2): 1710-1718, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30592414

RESUMO

In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD+ and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.


Assuntos
Compostos Ferrosos/farmacologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Lisossomos/metabolismo , Metalocenos/farmacologia , Imagem Óptica , Compostos Organometálicos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Células A549 , Antineoplásicos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Metalocenos/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Orgânicos de Estanho/química
10.
J Inorg Biochem ; 191: 49-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30458368

RESUMO

The objective of the present study was to review the mechanisms of organotin-induced adipogenesis, obesity, and associated metabolic disturbances. Peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα) activation is considered as the key mechanism of organotin-induced adipogenesis. Particularly, organotin exposure results in increased adipogenesis both in cell and animal models. Moreover, transgenerational inheritance of organotin-induced obese phenotype was demonstrated in vivo. At the same time, the existing data demonstrate that organotin compounds (OTCs) induces aberrant expression of PPARγ-targeted genes, resulting in altered of adipokine, glucose transporter, proinflammatory cytokines levels, and lipid and carbohydrate metabolism. The latter is generally characterized by hyperglycemia and insulin resistance. Other mechanisms involved in organotin-induced obesity may include estrogen receptor and corticosteroid signaling, altered DNA methylation, and gut dysfunction. In addition to cellular effects, organotin exposure may also affect neural circuits of appetite regulation, being characterized by neuropeptide Y (NPY) up-regulation in parallel with of pro-opiomelanocortin (POMC), Agouti-related protein (AgRP), and cocaine and amphetamine regulated transcript (CART) down-regulation in the arcuate nucleus. These changes result in increased orexigenic and reduced anorexigenic signaling, leading to increased food intake. The existing data demonstrate that organotins are potent adipogenic agents, however, no epidemiologic studies have been performed to reveal the association between organotin exposure and obesity and the existing indirect human data are contradictory.


Assuntos
Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Compostos Orgânicos de Estanho/metabolismo , Adipogenia/efeitos dos fármacos , Apetite/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , PPAR gama/agonistas , Receptores Estrogênicos/metabolismo , Receptores X Retinoide/agonistas
11.
Biochim Biophys Acta Biomembr ; 1861(1): 316-326, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908139

RESUMO

Metarhizium robertsii, a butyltin-resistant filamentous fungus, can rapid and complete biodegradation of di- (DBT) and tributyltin (TBT) under conditions of intensive aeration and ascorbic acid supplementation. In this paper, lipidomic investigations were performed to find the membrane adaptations necessary for effective butyltins degradation. HPLC-MS/MS analysis showed that the phospholipid profile was greatly modified during M. robertsii batch cultivation (pO2 ≥ 20%), contributing to increased membrane fluidity and facilitated mass transfer, which could enhance butyltins biodegradation. Intensified biosynthesis of phospholipids, sphingolipids and ergosterol by the mycelia exposed to butyltins was noted. DIOC6(3) fluorescence intensity for TBT-treated mycelium increased 9-fold pointing to membrane hyperpolarization. Fluorescent studies showed improved membrane rigidity and integrity in response to butyltins presence. Vitamin C supplementation restored membrane composition and dynamic properties, followed by supposed acceleration of transport of monobutyltin and its biodegradation thus protecting the M. robertsii cells against oxidative and nitrosative stress.


Assuntos
Metarhizium/metabolismo , Compostos Orgânicos de Estanho/farmacologia , Compostos de Trialquitina/farmacologia , Adaptação Fisiológica , Ácido Ascórbico/farmacologia , Biodegradação Ambiental , Suplementos Nutricionais , Ergosterol/metabolismo , Bicamadas Lipídicas/metabolismo , Metarhizium/efeitos dos fármacos , Micélio/metabolismo , Estresse Nitrosativo , Oxirredução , Estresse Oxidativo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Propriedades de Superfície , Espectrometria de Massas em Tandem
12.
Chem Pharm Bull (Tokyo) ; 66(12): 1104-1113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504627

RESUMO

A series of organotin(IV) complexes was herein prepared and characterized. A one-pot synthetic strategy afforded reasonable to high yields, depending on the nature of the ligand. All new complexes were fully characterized by spectroscopic techniques, consisting of IR, MS and NMR (1H, 13C and 119Sn). The in vitro cytotoxicity tests demonstrated that the organotin complexes produced a greater inhibition, versus cisplatin (the positive control), of the growth of six human cancer cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous leukemia), HCT-15 (colorectal), MCF-7 (breast), MDA-MB-231 (breast) and SKLU-1 (non-small cell lung). The potency of this cytotoxic activity depended on the nature of the substituent bonded to the aromatic ring. All complexes exhibited excellent IC50 values. The test compounds were also screened in vitro for their antifungal effect against Candida glabrata and Candida albicans, showing minimum inhibitory concentration (MIC) values lower than those obtained for fluconazole. A brine shrimp bioassay was performed to examine the toxic properties. Molecular docking studies demonstrated that the organotin(IV) complexes bind at the active site of topoisomerase I in a similar manner to topotecan, sharing affinity for certain amino acid side chains (Ile535, Arg364 and Asp533), as well as for similar DNA regions (DA113, DC112 and DT10).


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Orgânicos de Estanho/síntese química , Compostos Orgânicos de Estanho/química , Relação Estrutura-Atividade
13.
Sci Rep ; 8(1): 16580, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410055

RESUMO

A selective colon cancer cell therapy was effectively achieved with catalase-mediated intra-cellular heterogeneous Fenton reactions triggered by cellular uptake of SnFe2O4 nanocrystals. The treatment was proven effective for eradicating colon cancer cells, whereas was benign to normal colon cells, thus effectively realizing the selective colon cancer cell therapeutics. Cancer cells possess much higher innate hydrogen peroxide (H2O2) but much lower catalase levels than normal cells. Catalase, an effective H2O2 scavenger, prevented attacks on cells by reactive oxygen species induced from H2O2. The above intrinsic difference between cancer and normal cells was utilized to achieve selective colon cancer cell eradication through endocytosing efficient heterogeneous Fenton catalysts to trigger the formation of highly reactive oxygen species from H2O2. In this paper, SnFe2O4 nanocrystals, a newly noted outstanding paramagnetic heterogeneous Fenton catalyst, have been verified an effective selective colon cancerous cell treatment reagent of satisfactory blood compatibility.


Assuntos
Neoplasias do Colo/metabolismo , Compostos Férricos/farmacologia , Peróxido de Hidrogênio/metabolismo , Compostos Orgânicos de Estanho/farmacologia , Células CACO-2 , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Compostos Férricos/química , Humanos , Nanopartículas Metálicas , Compostos Orgânicos de Estanho/química , Espécies Reativas de Oxigênio/metabolismo
14.
Gen Physiol Biophys ; 37(5): 589-596, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30307405

RESUMO

Both, the vitamin D3 receptor (VDR) and the peroxisome proliferator-activated receptor gamma (PPARγ), are ligand-inducible transcription factors that control expressions of various genes involved in essential biological processes. Structurally diverse chemical substances are capable to bind to VDR and PPARγ, consequently acting in agonistic or antagonistic mode. Ubiquitous triorganotin compounds, key components of antifouling, disinfectant and biocidal agents were found to act as cognate ligands of several nuclear receptors. Triorganotins affect endocrine systems in disruptive manner recruiting proliferative, differentiation and apoptotic pathways. In this study, we have investigated agonistic as well as antagonistic effects of selected triorganotin compounds on VDR and PPARγ in transgenic gene reporter IZ-VDRE and PAZ-PPARγ human cell lines, allowing rapid and sensitive assessment of receptor transcriptional activity. We demonstrated that most of investigated triorganotins at nanomolar concentration exerted significant agonistic effects on VDR with fold activation ranging from 2.0 to 3.0-fold as well as some significant changes ranging from 127 to 199% of the maximal 1,25-dihydroxyvitamin D3 (calcitriol) induction, in antagonistic mode. In agonistic mode, PPARγ transcriptional activity was not affected by studied triorganotins significantly, but studied tributyltin compounds in antagonistic mode, revealed significant values ranging from 147 to 171% of the maximal 15-deoxy-δ12,14-prostaglandin J2 induction.


Assuntos
Compostos Orgânicos de Estanho/farmacologia , PPAR gama/genética , Receptores de Calcitriol/genética , Transcrição Genética/efeitos dos fármacos , Humanos
15.
Molecules ; 23(10)2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304779

RESUMO

Significant attention has been given to organotin(IV) dithiocabamate compounds in recent times. This is due to their ability to stabilize specific stereochemistry in their complexes, and their diverse application in agriculture, biology, catalysis and as single source precursors for tin sulfide nanoparticles. These complexes have good coordination chemistry, stability and diverse molecular structures which, thus, prompt their wide range of biological activities. Their unique stereo-electronic properties underline their relevance in the area of medicinal chemistry. Organotin(IV) dithiocabamate compounds owe their functionalities and usefulness to the individual properties of the organotin(IV) and the dithiocarbamate moieties present within the molecule. These individual properties create a synergy of action in the hybrid complex, prompting an enhanced biological activity. In this review, we discuss the chemistry of organotin(IV) dithiocarbamate complexes that accounts for their relevance in biology and medicine.


Assuntos
Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Varredura Diferencial de Calorimetria , Sobrevivência Celular , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Termogravimetria
16.
Molecules ; 23(7)2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29986449

RESUMO

Dibutyltin dilaurate (DBTD) has multiple applications in daily life. However, DBTD is easily deposited in the liver and affects liver functions. This study was designed to explore the effects of DBTD on triglyceride metabolism in human normal hepatocyte HL7702 cells. Our results showed that the intracellular fat contents were dose-dependently decreased by DBTD. The expression of lipolysis genes and proteins were elevated while the lipogenesis genes and proteins were diminished by DBTD. The phosphorylation levels of ribosomal S6 kinase 1 were reduced by both rapamycin and DBTD, indicating that the mTOR pathway was suppressed possibly. The decreased sterol regulatory element-binding protein 1C (SREBP1C) transcription levels, as well as the increased peroxisome proliferator-activated receptor alpha (PPARα) transcription levels, caused by rapamycin and DBTD corresponded to the inactive mTOR pathway. In conclusion, it was possible that DBTD reduced the intracellular triglyceride through depressing the mTOR pathway and affecting its downstream transcription factors.


Assuntos
Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triglicerídeos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , PPAR alfa/genética , Fosforilação/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
17.
Int J Mol Sci ; 19(7)2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30011935

RESUMO

Two known tin-based polymers of formula {[R3Sn(CH3COO)]n} where R = n-Bu⁻ (1) and R = Ph⁻ (2),were evaluated for their in vitro biological properties. The compounds were characterized via their physical properties and FT-IR, 119Sn Mössbauer, and ¹H NMR spectroscopic data. The molecular structures were confirmed by single-crystal X-Ray diffraction crystallography. The geometry around the tin(IV) ion is trigonal bi-pyramidal. Variations in O⁻Sn⁻O···Sn' torsion angles lead to zig-zag and helical supramolecular assemblies for 1 and 2, respectively. The in vitro cell viability against human breast adenocarcinoma cancer cell lines: MCF-7 positive to estrogens receptors (ERs) and MDA-MB-231 negative to ERs upon their incubation with 1 and 2 was investigated. Their toxicity has been studied against normal human fetal lung fibroblast cells (MRC-5). Compounds 1 and 2 exhibit 134 and 223-fold respectively stronger antiproliferative activity against MDA-MB-231 than cisplatin. The type of the cell death caused by 1 or 2 was also determined using flow cytometry assay. The binding affinity of 1 and 2 towards the CT-DNA was suspected from the differentiation of the viscosity which occurred in the solution containing increasing amounts of 1 and 2. Changes in fluorescent emission light of Ethidium bromide (EB) in the presence of DNA confirmed the intercalation mode of interactions into DNA of both complexes 1 and 2 which have been ascertained from viscosity measurements. The corresponding apparent binding constants (Kapp) of 1 and 2 towards CT-DNA calculated through fluorescence spectra are 4.9 × 104 (1) and 7.3 × 104 (2) M-1 respectively. Finally, the type of DNA binding interactions with 1 and 2 was confirmed by docking studies.


Assuntos
DNA/química , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Compostos Orgânicos de Estanho/química , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Humanos , Células MCF-7 , Compostos Orgânicos de Estanho/metabolismo , Compostos Orgânicos de Estanho/farmacologia
18.
Pak J Pharm Sci ; 31(4): 1399-1405, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30033426

RESUMO

The total phenolic content, flavonoid content, in vitro xanthine oxidase (XOD) inhibitory activity and antioxidant activity (AA) of Eucommia ulmoides Oliver leaf extracts were investigated. The AA investigations included 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, ß-carotene/linoleic acid bleaching assay and oxygen radical absorbance capacity (ORAC) test. The ethyl acetate fraction (EE) showed the highest AA and xanthine oxidase inhibitory activity. Whilst the lowest 50% inhibition (IC50) value of this fraction for DPPH free radical scavenging was 0.045mg/mL, its highest ORAC value was 10.57 µmol TE/mg. The highest inhibition rate against linoleic acid oxidation observed was 69.41%, and the lowest IC50 value for xanthine oxidase activity inhibition was 2.47mg/mL. These results show that E. ulmoides leaf extract is a promising source of natural antioxidants because it contains high contents of bioactive compounds, including chlorogenic acid, rutin, hyperin and astragalin, as detected by high-performance liquid chromatography coupled to HPLC-DAD-ESI-MS.


Assuntos
Anti-Infecciosos/síntese química , Inibidores Enzimáticos/síntese química , Compostos Orgânicos de Estanho/síntese química , Urease/antagonistas & inibidores , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/farmacologia , Bases de Schiff/química
19.
Environ Health Perspect ; 126(5): 057006, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29787037

RESUMO

BACKGROUND: The organotin dibutyltin (DBT) is used in the manufacture of polyvinyl chloride (PVC) plastics, in construction materials, and in medical devices. Previous animal studies showed detrimental effects of DBT during in utero development at relatively high doses, but little was known about the effects of DBT exposure at environmentally relevant doses on endpoints such as obesity and metabolic disease. OBJECTIVES: We tested the potential obesogenic effects of DBT using in vitro and in vivo models. METHODS: We evaluated the effects of DBT on nuclear receptor activation and adipogenic potential using human and mouse multipotent mesenchymal stromal stem cells (MSCs). We also evaluated the effects of perinatal exposure to environmentally relevant doses of DBT in C57BL/6J mice. RESULTS: DBT activated human and mouse PPARγ and RXRα in transient transfection assays, increased expression of adipogenic genes, promoted adipogenic differentiation and increased lipid accumulation in mouse and human MSCs, in vitro. DBT-induced adipogenic differentiation was abolished by the PPARγ antagonist T0070907, indicating that DBT was acting primarily through PPARγ. Perinatal exposure to low doses of DBT led to increased fat storage, decreased glucose tolerance, and increased circulating leptin levels in male, but not female, mice. CONCLUSIONS: DBT acted as an obesogen by inducing lipid accumulation in human and mouse MSCs through a PPARγ-dependent pathway. In vivo exposure to biologically relevant doses of DBT during perinatal development led to increased fat storage, elevated leptin levels in plasma, and glucose intolerance in mice. Based on these findings, we posit that monitoring of DBT levels in human samples may aid in understanding and potentially preventing the rising rates of metabolic disorders in human populations. https://doi.org/10.1289/EHP3030.


Assuntos
Glucose/metabolismo , Compostos Orgânicos de Estanho/farmacologia , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Inorg Chem ; 57(11): 6340-6348, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29792415

RESUMO

Antibacterial agents with two-photon absorption are expected to play a significant role in biomedical science. Herein, two novel organotin complexes, HLSn1 and HLSn2, based on coumarin were designed, synthesized, and systematically investigated. It was found that these complexes possessed suitable two-photon-active cross sections in the near-infrared region. Moreover, complex HLSn1 could efficiently inhibit the growth of Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, especially the latter with a minimum inhibitory concentration (MIC; 90%) of 2 ± 0.14 µg mL-1, which is lower than that of Kanamycin (Kana, 8 ± 0.42 µg mL-1). Importantly, two-photon imaging and superresolution development of bacterial stain revealed that complex HLSn1 can react with bacterial membranes, producing reactive oxygen species (ROS) and leading to cell death. These outcomes provide promising applications in the superresolution bacteria imaging, diagnostics, and treatment of bacterial infectious.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Cumarínicos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Estanho , Antibacterianos/química , Antibacterianos/toxicidade , Bacillus subtilis/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cumarínicos/química , Cumarínicos/toxicidade , Escherichia coli/efeitos dos fármacos , Fluorescência , Testes de Sensibilidade Microbiana , Estrutura Molecular , Imagem Óptica , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/toxicidade
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