RESUMO
Organotin(IV) and iridium(III) complexes have shown good application potential in the field of anticancer; however, the aggregation-caused quenching (ACQ) effect induced by high concentration or dose has limited the research on their targeting and anticancer mechanism. Then, a series of aggregation-induced emission (AIE)-activated butyltin(IV)-iridium(III) imidazole-phenanthroline complexes were prepared in this study. Complexes exhibited significant fluorescence improvement in the aggregated state because of the restricted intramolecular rotation (RIR), accompanied by an absolute fluorescence quantum yield of up to 29.2% (IrSn9). Complexes demonstrated potential in vitro antiproliferative and antimigration activity against A549 cells, following a lysosomal-mitochondrial apoptotic pathway. Nude mouse models further confirmed that complexes had favorable in vivo antitumor and antimigration activity in comparison to cisplatin. Therefore, butyltin(IV)-iridium(III) imidazole-phenanthroline complexes possess the potential as potential substitutes for platinum-based drugs.
Assuntos
Antineoplásicos , Proliferação de Células , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Imidazóis , Irídio , Fenantrolinas , Fenantrolinas/química , Fenantrolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Animais , Camundongos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Proliferação de Células/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Irídio/química , Irídio/farmacologia , Camundongos Nus , Apoptose/efeitos dos fármacos , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/síntese química , Estrutura Molecular , Células A549RESUMO
Many diorganotin complexes with various alkyl groups exhibit excellent in vitro anticancer activity. However, most diorganotin is the same alkyl group, and the asymmetric alkyl R group has been rarely reported. Hence, in this paper, twenty butylphenyl mixed dialkyltin arylformylhydrazone complexes have been synthesized by microwave "one-pot" reaction with arylformylhydrazine, substituted α-keto acid or its sodium salt and butylphenyltin dichloride. The crystal structures of nine complexes were determined, indicating that the complexes C1, C2, C11, C12, and C16 â¼ C19 possessed a central symmetric structure of a dinuclear Sn2O2 tetrahedral ring; while the complex C9 is a trinuclear tin-oxygen cluster with a 6-membered ring encased in a 12-membered macrocyclic structure. The inhibiting activity of complexes was tested against the human cell lines NCI-H460, MCF-7, HepG2, Huh-7 and HL-7702. Complex C2 demonstrated the optimal inhibitory effect on HepG2 cells, with an IC50 value of 0.82 ± 0.03 µM. Cellular biology experiments revealed that complex C2 could induce apoptosis and G2/M phase cell cycle arrest in HepG2 and Huh-7 cells. The complex also caused the collapse of the mitochondrial membrane potential and increased intracellular reactive oxygen species in HepG2 and Huh-7 cells. Western blot analysis further clarified that complex C2 could induce cell apoptosis through the mitochondrial pathway along with the release of reactive oxygen species.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Hidrazonas , Compostos Orgânicos de Estanho , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Three distinctive end group-containing organotin (IV) carboxylates complexes (YDCOOSn, CLCOOSn and BZCOOSn) were designed and synthesized. Together with theoretical calculations, a thorough examination was carried out to investigate the photophysical properties of these compounds. The cytotoxicity of the synthesized compounds was tested using normal cell line GES-1 and was assessed against four cancer cell lines (A549, Hela, H1299 and HepG2). The outcomes of the experiments demonstrated that these complexes had superior selectivity than cisplatin towards cancerous cells, particularly in the A549 cell line. BZCOOSn was selected as a candidate compound for additional research because it exhibited the lowest IC50 value and the most impressive inducing effect on cell death and G2/M phase arrest. Increased caspase-3 and -9 enzyme activity, a decline in mitochondrial membrane potential (MMP), characteristic nuclear apoptotic morphology, and an accumulation of intracellular reactive oxygen species (ROS) were seen in A549 exposed to BZCOOSn. These findings demonstrated that BZCOOSn exhibited strong cytotoxicity by triggering cell death in A549 via the mitochondrial route. Furthermore, using the scratch wound healing assay, it was discovered that BZCOOSn reduced the migration of A549 cancerous cells. These data all pointed to BZCOOSn as a possible candidate for more research and development as a chemotherapeutic drug.
Assuntos
Antineoplásicos , Apoptose , Potencial da Membrana Mitocondrial , Compostos Orgânicos de Estanho , Espécies Reativas de Oxigênio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/síntese química , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células A549 , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Linhagem Celular Tumoral , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Movimento Celular/efeitos dos fármacos , Células HeLaRESUMO
Organotins have been widely used in various industrial applications. This study investigated the structure-activity relationship as inhibitors of human, pig, and rat gonadal 3ß-hydroxysteroid dehydrogenases (3ß-HSD). Human KGN cell, pig, and rat testis microsomes were utilized to assess the inhibitory effects of 18 organotins on the conversion of pregnenolone to progesterone. Among them, diphenyltin, triethyltin, and triphenyltin exhibited significant inhibitory activity against human 3ß-HSD2 with IC50 values of 114.79, 106.98, and 5.40 µM, respectively. For pig 3ß-HSD, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin demonstrated inhibitory effects with IC50 values of 172.00, 100.19, 87.00, 5.75, and 1.65 µM, respectively. Similarly, for rat 3ß-HSD1, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin displayed inhibitory activity with IC50 values of 81.35, 43.56, 55.55, 4.09, and 0.035 µM, respectively. They were mixed inhibitors of pig and rat 3ß-HSD, while triphenyltin was identified as a competitive inhibitor of human 3ß-HSD2. The mechanism underlying the inhibition of organotins on 3ß-HSD was explored, revealing that they may disrupt the enzyme activity by binding to cysteine residues in the catalytic sites. This proposition was supported by the observation that the addition of dithiothreitol reversed the inhibition caused by all organotins except for triethyltin, which was partially reversed. In conclusion, this study provides valuable insights into the structure-activity relationship of organotins as inhibitors of human, pig, and rat gonadal 3ß-HSD. The mechanistic investigation suggests that these compounds likely exert their inhibitory effects through binding to cysteine residues in the catalytic sites.
Assuntos
Inibidores Enzimáticos , Compostos Orgânicos de Estanho , Testículo , Animais , Humanos , Relação Estrutura-Atividade , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/química , Ratos , Masculino , Testículo/enzimologia , Testículo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Suínos , 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 3-Hidroxiesteroide Desidrogenases/metabolismo , Simulação de Acoplamento Molecular , Progesterona/farmacologia , Progesterona/metabolismo , Microssomos/enzimologia , Microssomos/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Nine new organotin (IV) derivatives from L-amino acids (l-lysine, L-ornithine, L-glutamic acid, and L-aspartic acid) were synthesized by one-pot ultrasound-assisted methodology. All compounds were characterized by ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared), LRMS (Low-Resolution Mass Spectrometry), and solution NMR (1H, 13C, 119Sn Nuclear Magnetic Resonance) spectroscopies. Complexes Bu2Sn(Lys) (1), Ph2Sn(Lys) (2), Bu2Sn(Orn) (3), and Ph2Sn (Glu-OMe) (6a) were crystallized, and the structures were established by single-crystal X-ray diffraction analysis. Diffraction results evidenced that complexes 1 to 3 were five-coordinated mononuclear species while the phenyl substituted derivative Ph2Sn (Glu-OMe) (6a) forms a polymeric network via Sn-O-Sn bridging whereby the tin atom is six-coordinated. In turn, 119Sn NMR results revealed that all tin complexes exist as mononuclear penta-coordinated species in solution. The tin derivatives were screened for ADME (Adsorption, Distribution, Metabolism, and Excretion) properties via the freely available tools SWISS ADME, and the results were analyzed hereafter. The antiproliferative activity of the complexes was tested against three human cancer cell lines: colorectal adenocarcinoma HT-29, breast adenocarcinoma MDA-MB-231, and chondrosarcoma SW-1353 using a non-tumoral cell line of human osteoblast as control, demonstrating selective inhibitory activities against cancer cells. Hence, these compounds could be a promising alternative to classical chemotherapy agents.
Assuntos
Aminoácidos , Antineoplásicos , Compostos Orgânicos de Estanho , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/síntese química , Aminoácidos/química , Aminoácidos/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
BACKGROUND: Organotin(IV) complexes of dithiocarbamate are vital in medicinal chemistry, exhibiting potential in targeting cancer cells due to their unique properties that enhance targeted delivery. This study aimed to synthesize and characterize organotin(IV) N-ethyl-N-benzyldithiocarbamate complexes (ONBDCs) and evaluate their cytotoxicity against A549 cells, which are commonly used as a model for human lung cancer research. METHODS: The two ONBDC derivatives - ONBDC 1 (dimethyltin(IV) N-ethyl-N-benzyldithiocarbamate) and ONBDC 2 (triphenyltin(IV) N-ethyl-N-benzyldithiocarbamate) - were synthesized via the reaction of tin(IV) chloride with N-ethylbenzylamine in the presence of carbon disulfide. A range of analytical techniques, including elemental analysis, IR spectroscopy, NMR spectroscopy, UV-Vis spectrometry, TGA/DTA analysis, and X-ray crystallography, was conducted to characterize these compounds comprehensively. The cytotoxic effects of ONBDCs against A549 cells were evaluated using MTT assay. RESULTS: Both compounds were synthesized and characterized successfully via elemental and spectroscopies analysis. MTT assay revealed that ONBDC 2 demonstrated remarkable cytotoxicity towards A549 cells, with an IC50 value of 0.52 µM. Additionally, ONBDC 2 displayed significantly higher cytotoxic activity against the A549 cell line when compared to the commercially available chemotherapeutic agent cisplatin (IC50: 32 µM). CONCLUSION: Thus, it was shown that ONBDC 2 could have important anticancer properties and should be further explored as a top contender for creating improved and specialized cancer treatments.
Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Orgânicos de Estanho , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Células A549 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Tiocarbamatos/química , Tiocarbamatos/farmacologia , Tiocarbamatos/síntese química , Desenvolvimento de MedicamentosRESUMO
Three newly synthesized triphenyltin(IV) compounds, Ph3SnL1 (L1- = 3-(4-methyl-2-oxoquinolin-1(2H)-yl)propanoato), Ph3SnL2 (L2- = 2-(4-methyl-2-oxoquinolin-1(2H)-yl)ethanoato), and Ph3SnL3 (L3- = 2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethanoato), were characterized by elemental microanalysis, FT-IR spectroscopy and multinuclear (1H, 13C and 119Sn) NMR spectroscopy. A single X-ray diffraction study indicates that compounds Ph3SnL1 and Ph3SnL2 exhibit a 1D zig-zag chain polymeric structure, which in the case of Ph3SnL2 is additionally stabilized by π-interactions. In addition, the synthesized compounds were further examined using density functional theory and natural bond orbital analysis. The compounds have been evaluated for their in vitro anticancer activity against three human cell lines: MCF-7 (breast adenocarcinoma), A375 (melanoma), HCT116 (colorectal carcinoma), and three murine cell lines: 4T1 (breast carcinoma), B16 (melanoma), CT26 (colon carcinoma) using MTT and CV assays. The IC50 values fall in the nanomolar range, indicating that these compounds possess better anticancer activity than cisplatin. The study of the effect of the newly developed drug Ph3SnL1 showed its plasticity in achieving an antitumor effect in vitro, which depends on the specificity of the phenotype and the redox status of the malignant cell line and ranges from the initiation of apoptotic cell death to the induction of differentiation to a more mature cell form. In the syngeneic model of murine melanoma, Ph3SnL1 showed the potential to reduce the tumor volume similar to cisplatin, but in a well-tolerated form and with low systemic toxicity, representing a significant advantage over the conventional drug.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Orgânicos de Estanho , Quinolonas , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Animais , Camundongos , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Teoria da Densidade Funcional , Estrutura Molecular , Relação Estrutura-Atividade , Sobrevivência Celular/efeitos dos fármacosRESUMO
Organotin compounds (OTCs) are widely regulated but rank among the most used organometallic compounds in various industrial sectors. They are significantly more toxic than inorganic tin compounds. At workplaces, OTCs can be released as vapors or dust particles and can be absorbed by inhalation or skin contact. Occupational exposure thus represents a great risk for the absorption of OTCs for employees. Methods for OTCs speciation in workplace air monitoring currently do not exist. This study describes the development of a separation method for eleven in Germany regulated OTCs via HPLC-ICP-MS. The method allows a near baseline separation of MMT, MBT, MOT, MPhT, DMT, DBT, DPhT, TMT, TBT, TPhT and TTMT within 22 min on a C18 column and a ternary solvent and flow rate gradient using methanol, acetonitrile, and ultrapure water + 6% (v/v) acetic acid + 0.17% (m/v) α-tropolone. Ten analytes show linearity in the working range of 10 - 100 µg OTCs/L with R² > 0.999. Due to its high volatility the analyte TTMT showed a quadratic relationship between concentration and signal intensity with R² = 0.9998. The determination of the instrumental limits resulted in detection limits between 0.14 and 0.57 µg Sn/L and limits of quantification between 0.49 and 1.97 µg Sn/L. Over the course of this study thermal instability and cross reactivity of OTC in solution became apparent. Formation of two reaction products in mixed OTCs solutions have been observed. These effects will further be examined within development of appropriate sampling and sample preparation for workplace air to provide a suitable method for the determination of OTCs at workplaces according to normative references.
Assuntos
Exposição Ocupacional , Compostos Orgânicos de Estanho , Telúrio , Humanos , Compostos Orgânicos de Estanho/análise , Cromatografia Líquida de Alta Pressão , Local de Trabalho , Exposição Ocupacional/análiseRESUMO
INTRODUCTION: Continuous research for new effective drugs to treat cancer has improved our understanding on the mechanism of action of these drugs and paved new potential for their application in cancer treatments. In this study, organotin compounds known as triphenyltin ethyl phenyl dithiocarbamate and triphenyltin butyl phenyl dithiocarbamate were investigated for their toxicity on leukemia cell line (K562) and non-cancerous cell line (Chang liver cell and lung fibroblast, V79 cell). METHODS: MTT assay was performed to evaluate the cytotoxic effects of both compounds toward the cells after 24, 48 and 72 hours of exposure or treatment. The alkaline comet assay was conducted to determine the DNA damage on K562 cells after been exposed to both compounds for 30, 60 and 90 minutes. RESULTS: The IC50 values obtained from K562 cells ranged from 0.01 to 0.30 µM, whereas for both Chang liver cell and lung fibroblast V79 cell, the values ranged from 0.10 to 0.40 µM. For genotoxicity evaluation, the percentage of damaged DNA is measured as an average of tail moment, and was found to be within 1.20 to 2.20 A.U while the percentage of DNA intensity ranging from 1.50 to 3.50% indicating no genotoxic effects. CONCLUSION: Both compounds are cytotoxic toward leukemia cells and non-cancerous cells but do not exert their genotoxic effects towards leukemia cell.
Assuntos
Antineoplásicos , Leucemia , Compostos Orgânicos de Estanho , Humanos , Células K562 , Compostos Orgânicos de Estanho/farmacologia , Dano ao DNA , Antineoplásicos/farmacologia , Leucemia/tratamento farmacológicoRESUMO
A series of novel dibutyltin complexes based on salen-like ligands (S01-S03) were synthesized and characterized using ultraviolet-visible spectraï¼infrared spectra, 1H, 13C, and 119Sn nuclear magnetic resonance, high-resolution mass spectrometry, X-ray crystallography, and thermogravimetric analysis. Complex S03 had excellent anticancer activity in vitro (IC50 = 1.5 ± 0.2 µM in CAL-27 cell lines), which highly activated ROS expression levels and induced apoptosis and cell cycle arrest at the G2/M phase. Interestingly, complex S03 induced cancer cell death through multiple mechanisms (mitochondrial pathway, ER-stress pathway, and DNA damage pathway). This study reveals new mechanisms of organotin complexes and provides new insights into the development of organotin metal complexes as anticancer drugs in the future, and compounds with multiple anticancer mechanisms may be a new strategy for delaying or overcoming drug resistance to chemotherapy and target therapy.
Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Orgânicos de Estanho , Compostos Orgânicos de Estanho/química , Antineoplásicos/química , Etilenodiaminas/farmacologia , Complexos de Coordenação/química , Linhagem Celular Tumoral , Apoptose , LigantesRESUMO
Triphenyltin is an environmental contaminant widely used in antifouling paints and can cause toxicity in various organs in living organisms. However, its effects on intestinal function and the microbiome of the gut remain unknown. The objective of this study was to explore the intestinal toxicity of triphenyltin in mice by orally administering 0, 1.875, 3.75, and 7.5 mg/Kg to adult male mice for 8 weeks. Results showed that triphenyltin caused ileum tissue damage, induced oxidative stress, upregulated inflammation-related gene expression and increased serum tumor-necrosis factor α (TNF-α) levels in mice. Triphenyltin impaired ileum barrier function by downregulating Muc2, ZO-1, Occludin and their protein levels at 3.75 and 7.5 mg/Kg. TPT exposure led to partial inflammation and decreased mucin mRNA expression in the colon. Triphenyltin altered intestinal micro-ecological balance and fecal metabolome in mice. In conclusion, triphenyltin alters the mouse gut microbiota and fecal metabolome.
Assuntos
Microbioma Gastrointestinal , Compostos Orgânicos de Estanho , Masculino , Camundongos , Animais , Compostos Orgânicos de Estanho/toxicidade , Inflamação , FezesRESUMO
Triphenyltin chloride (TPT-Cl) is an organometallic organotin. This study aimed to investigate the role of trigonelline (TG) along with the impact of TPT withdrawal on the testicular toxicity induced by TPT-Cl. Thirty-six adult male albino rats were divided into control, TG (40â mg/kg/day), TPT-Cl (0.5â mg/kg/day), TG + TPT-Cl, and recovery groups. Animals were daily gavaged for 12 weeks. Both TG and TPT-Cl withdrawal improved TPT-Cl-induced testicular toxicity features involving testis and relative testis weight reduction, luteinizing hormone, follicular stimulating hormone, and sex hormone-binding globulin elevation, reduction of inhibin B, free testosterone levels, and sperm count reduction with increased abnormal sperm forms. Moreover, both TG and TPT-Cl withdrawal reduced inflammatory activin A, follistatin, tumor necrosis factor α, interleukin-1ß, and proapoptotic Bax and elevated antiapoptotic Bcl2 in testicular tissues mediated by TPT-Cl. TG and TPT-Cl withdrawal restored the excessive autophagy triggered by TPT-Cl via elevation of mTOR, AKT, PI3K, and P62/SQSTM1 and reduction of AMPK, ULK1, Beclin1, and LC3 mRNA gene expressions and regained the deteriorated testicular structure. In conclusion, TG and TPT-Cl withdrawal had an ameliorative role in partially reversing TPT-Cl-induced testicular toxicity. However, the findings indicated that the use of TG as an adjunctive factor is more favorable than TPT-Cl withdrawal, suggesting the capability of the testis for partial self-improvement.
Assuntos
Alcaloides , Compostos Orgânicos de Estanho , Testículo , Testosterona , Ratos , Animais , Masculino , Testículo/patologia , Testosterona/metabolismo , Sêmen/metabolismo , Apoptose , Autofagia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse OxidativoRESUMO
Trimethyltin chloride (TMT) is a highly toxic organotin compound often used in plastic heat stabilizers, chemical pesticides, and wood preservatives. TMT accumulates mainly through the environment and food chain. Exposure to organotin compounds is associated with disorders of glucolipid metabolism and obesity. The mechanism by which TMT damages pancreatic tissue is unclear. For this purpose, a subacute exposure model of TMT was designed for this experiment to study the mechanism of damage by TMT on islet. The fasting blood glucose and blood lipid content of mice exposed to TMT were significantly increased. Histopathological and ultrastructural observation and analysis showed that the TMT-exposed group had inflammatory cell infiltration and necrosis. Then, mouse pancreatic islet tumour cells (MIN-6) were treated with TMT. Autophagy levels were detected by fluorescence microscopy. Real-time quantitative polymerase chain reaction and Western blotting were used for verification. A large amount of autophagy occurred at a low concentration of TMT but stagnated at a high concentration. Excessive autophagy activates apoptosis when exposed to low levels of TMT. With the increase in TMT concentration, the expression of necrosis-related genes increased. Taken together, different concentrations of TMT induced apoptosis and necrosis through autophagy disturbance. TMT impairs pancreatic (islet ß cell) function.
Assuntos
Compostos Orgânicos de Estanho , Compostos de Trimetilestanho , Animais , Camundongos , Apoptose , Necrose/induzido quimicamente , Compostos de Trimetilestanho/toxicidade , Autofagia , Compostos Orgânicos de Estanho/toxicidadeRESUMO
Organotin (IV) dithiocarbamate has recently received attention as a therapeutic agent among organotin (IV) compounds. The individual properties of the organotin (IV) and dithiocarbamate moieties in the hybrid complex form a synergy of action that stimulates increased biological activity. Organotin (IV) components have been shown to play a crucial role in cytotoxicity. The biological effects of organotin compounds are believed to be influenced by the number of Sn-C bonds and the number and nature of alkyl or aryl substituents within the organotin structure. Ligands target and react with molecules while preventing unwanted changes in the biomolecules. Organotin (IV) dithiocarbamate compounds have also been shown to have a broad range of cellular, biochemical, and molecular effects, with their toxicity largely determined by their structure. Continuing the investigation of the cytotoxicity of organotin (IV) dithiocarbamates, this mini-review delves into the appropriate method for synthesis and discusses the elemental and spectroscopic analyses and potential cytotoxic effects of these compounds from articles published since 2010.
Assuntos
Antineoplásicos , Compostos Orgânicos de Estanho , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/químicaRESUMO
Although restricting environmental quality values for organotin compounds (OTs) are set by Directive 2013/39/EU of the European Parliament, marine environment remains being affected due to maritime circulation at global scale. Fish and seafood accumulate OTs, making fish and seafood consumption the main source of OTs in humans. Because of the fish and seafood matrices complexity and the required low limits of detection, a robust and fast procedure for the quantification of OTs in fish and seafood, using ultrasound-assisted extraction and gas chromatography-tandem mass spectrometry, was validated and applied. Detection (2.7 µg Sn kg-1) and quantification (8.0 µg Sn kg-1) limits, repeatability and intermediate precision (<10%), accuracy by analysing ERM®-CE477 Mussel Tissue and analytical recoveries (65-122%) were assessed. Multivariate analysis shown that the matrix effect for some OTs displayed good negative correlation with the fat and protein content. Health risk assessment of OTs intake revealed no serious risk for human consumption.
Assuntos
Compostos Orgânicos de Estanho , Animais , Humanos , Compostos Orgânicos de Estanho/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Espectrometria de Massas em Tandem/métodos , Ultrassom , Contaminação de Alimentos/análise , Peixes/metabolismo , Alimentos Marinhos/análiseRESUMO
A number of novel di- and triorganotin(IV) complexes 1-5 (Ph2SnL1, Ph2SnL2, Et2SnL2, Ph3SnL3, Ph3SnL4) with mono- or dianionic forms of thio-Schiff bases containing antioxidant sterically hindered phenol or catechol fragments were synthesized. Compounds 1-5 were characterized by 1H, 13C NMR, IR spectroscopy, and elemental analysis. The molecular structures of complexes 1 and 2 in the crystal state were established by single-crystal X-ray analysis. The antioxidant activity of new complexes as radical scavengers was estimated in DPPH and ABTS assays. It was found that compounds 4 and 5 with free phenol or catechol fragments are more active in these tests than complexes 1-3 with tridentate O,N,S-coordinated ligands. The effect of compounds 1-5 on the promoted oxidative damage of the DNA by 2,2'-azobis(2-amidinopropane) dihydrochloride and in the process of rat liver (Wistar) homogenate lipid peroxidation in vitro was determined. Complexes 4 and 5 were characterized by more pronounced antioxidant activity in the reaction of lipid peroxidation in vitro than compounds 1-3. The antiproliferative activity of compounds 1-5 was investigated against MCF-7, HTC-116, and A-549 cell lines by an MTT test. The values of IC50 are significantly affected by the presence of free antioxidant fragments and the coordination site for binding.
Assuntos
Complexos de Coordenação , Compostos Orgânicos de Estanho , Ratos , Animais , Antioxidantes/farmacologia , Fenol , Bases de Schiff/química , Ratos Wistar , Compostos Orgânicos de Estanho/química , Fenóis/farmacologia , Catecóis/farmacologia , Complexos de Coordenação/química , LigantesRESUMO
Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.
Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Orgânicos de Estanho , Compostos de Trialquitina , Cisplatino , Linhagem Celular Tumoral , Compostos de Trialquitina/farmacologia , Antineoplásicos/farmacologia , Compostos Orgânicos de Estanho/farmacologiaRESUMO
The discovery of cisplatin has influenced scientists to study the anticancer properties of other metal complexes. Organotin(IV) dithiocarbamate compounds are gaining attention as anticancer agents due to their potent cytotoxic properties on cancer cells. In this study, a series of organotin compounds were assessed for their toxic effects on the Jurkat E6.1 cell line. WST-1 assay was used to determine the cytotoxic effect of the compounds and showed that six out of seven organotin(IV) dithiocarbamate compounds exhibited potent cytotoxic effects toward T-lymphoblastic leukemia cells, Jurkat E6.1 with the concentration of IC50 ranging from 0.67-0.94 µM. The apoptosis assay by Annexin V-FITC/PI staining showed that all tested compounds induced cell death mainly via apoptosis. Cell cycle analysis assessed using RNase/PI staining showed that organotin(IV) dithiocarbamate compounds induced cell cycle arrest at different phases. In conclusion, the tested organotin(IV) dithiocarbamate compounds demonstrated potent cytotoxicity against Jurkat E6.1 cells via apoptosis and cell cycle arrest at low IC50 value. However, further studies on the mechanisms of action are required to probe the possible potential of these compounds on leukemia cells before they can be developed into anti-leukemic agents.
Assuntos
Antineoplásicos , Compostos Orgânicos de Estanho , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Pontos de Checagem do Ciclo Celular , Apoptose , Antineoplásicos/farmacologia , Células Jurkat , Compostos Orgânicos de Estanho/farmacologia , Linhagem Celular TumoralRESUMO
A series of novel organotin(IV) complexes on the base of 2-(N-3',5'-di-tert-butyl-4'-hydroxyphenyl)-iminomethylphenol (L) of formulae Me2SnBr2(L)2 (1), Bu2SnCl2(L)2(2), Ph2SnCl2(L) (3), Ph2SnCl2(L)2 (4) Ph3SnBr(L)2 (5) were synthesized and characterized by 1H, 13C, 119Sn NMR, IR, ESI-MS and elemental analysis. The crystal structures of initial L and complex 2 were determined by XRD method. It was found that L crystallizes in the orthorhombic syngony. The distorted octahedron geometry around Sn center is observed in the structure of complex 2. Intra- and inter-molecular hydrogen bonds were found in both structures. The antioxidant activity of new complexes as reducing agents, radical scavengers and lipoxygenase inhibitors was estimated spectrophotometrically in CUPRAC and DPPH tests (compounds 1 and 5 were found to be the most active in both methods), and in the process of enzymatic oxidation in vitro of linoleic acid under the action of lipoxygenase LOX 1-B (EC50 > 33.3 µM for complex 2). Furthermore, compounds 1-5 have been investigated for their antiproliferative activity in vitro towards HCT-116, MCF-7 and A-549 and non-malignant WI-38 human cell lines. Complexes 2 and 5 demonstrated the highest activity. The plausible mechanisms of the antiproliferative activity of compounds, including the influence on the polymerization of Tb+MAP, are discussed. Some of the synthesized compounds have also actively induced apoptosis and blocked proliferation in the cell cycle G2/M phase.
Assuntos
Antineoplásicos , Compostos Orgânicos de Estanho , Humanos , Antioxidantes/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Compostos Orgânicos de Estanho/química , Bases de Schiff/farmacologia , Bases de Schiff/química , Cristalografia por Raios X , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: Cancer cases have escalated by approximately 12% since 1900 and the incidence rate has increased faster for females than males. The discovery of cisplatin in 1965 paved the way for metal-based compounds as cancer therapeutics. Unfortunately, cisplatin and other platinum-based medicines cause severe side effects. Therefore, non-platinum metal complexes have been developed as alternate cancer drugs. Among non-platinum metal complexes, organotins are the most effective candidates in oncology due to their wide range of anticancer activities with relatively minimal toxicities towards healthy cells, better excretion from the body, and fewer side effects than platinum drugs. METHODS: Using DOI searching, advances made by organotin(IV) complexes coordinated with Sn-O, Sn-N and Sn-S as chemotherapeutic agents since 2018 are summarized in this article. Their chemical structure and in vitro antiproliferative activity in terms of IC50/EC50/LD50 are cumulated. RESULTS: As reflected in this perspective, organotin(IV) complexes are found to induce high cell death via apoptosis, and also several complexes demonstrated anticancer activity even higher than standard drugs. CONCLUSION: Undoubtedly, the organotin(IV) complexes could bring hope to morbidity and mortality of human beings caused by fast-spreading cancer worldwide and can play an important role in drug discovery.