RESUMO
Organosulfur compounds derived from plants of the Allium genus, such as propyl-propane-thiosulfinate (PTS) and propyl-propane-thiosulfonate (PTSO), have been proposed as an alternative in antibiotic resistance. The aim of this study was to compare the activity of these substances with other antibiotics against clinical isolates of carbapenem-resistant (CAR-R) and carbapenem-susceptible (CAR-S) Gram-negative bacteria. A total of 126 clinical isolates of CAR-R and 155 CAR-S bacteria were selected, including Enterobacterales, A. baumannii and P. aeruginosa. The antibiotic susceptibility of all isolates was assessed using the microdilution and Kirby-Bauer methods for PTS, PTSO, amoxicillin/clavulanate, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, ciprofloxacin, and amikacin. Both PTS and PTSO demonstrated in vitro bactericidal activity against CAR-R Enterobacteriaceae and A. baumannii, with no significant difference in activity compared to their response against CAR-S isolates. However, both compounds were less active against P. aeruginosa than against any of the other bacteria, regardless of their resistance to carbapenems. In all cases, the minimum inhibitory concentration values of PTSO were significantly lower than those of PTS. These findings offer valuable information about the potential antibacterial use of these substances, particularly against infections that currently have limited therapeutic options.
Assuntos
Antibacterianos , Carbapenêmicos , Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Humanos , Carbapenêmicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Acinetobacter baumannii/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , Allium/química , Ácidos Tiossulfônicos/farmacologia , Ácidos Sulfínicos/farmacologiaRESUMO
The organosulfur compounds (OSC) extracted from Allium spp. exhibit antibacterial, antifungal, and antioxidant properties. The agri-food industry is taking advantage of these properties by using them as natural feed and food additives. In the present work, an acute and a subchronic 90-days toxicity studies have been conducted for the first time to assess the safety of the OSC propyl-propane-thiosulfinate (PTS). Both studies were carried out following the Organization for Economic Co-operation and Development test guidelines (425 and 408, respectively). The acute study provided a maximum tolerated dose (MTD) of 175 mg/kg and the subchronic study established the Non Observed Adverse Effect Level (NOAEL) ≥ 55 mg/kg body weight (b.w.)/day in both sexes. In addition, the subchronic study performed on rats exposed to 14, 28 and 55 mg/kg b.w./day PTS, revealed no changes in any of the hematological parameters measured as well as no differences in body weight and water/food consumption. However, biochemical parameters were altered in some groups, although they were not biologically significant (Ca2+ in female rats, and the thyroids hormones T3 and T4 in rat males). Furthermore, the histopathological assessment evidenced no abnormality on the gastrointestinal, respiratory, lymphoid, urinary, circulatory, nervous, musculoskeletal, and reproductive systems.
Assuntos
Allium/química , Extratos Vegetais/farmacologia , Ácidos Tiossulfônicos/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Masculino , Extratos Vegetais/química , Ratos , Testes de ToxicidadeRESUMO
Propyl-propane-thiosulfonate (PTSO) and Propyl-propane-thiosulfinate (PTS) are organosulfur compounds used to supplement the diet of livestock because of their beneficial effects on feed palatability, their antibacterial, anti-inflammatory, and antimethanogenic activities. Besides, antibiotic residues in the environment can be reduced by using these natural bioactive compounds. The objective of this study was to optimize the extraction parameters for the analysis of PTSO and PTS in feed matrices by performing a solid-liquid extraction and quantification by Ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Optimization was performed using the Response Surface Methodology on a Box-Behnken experimental design, optimizing the following parameters: solvent:sample ratios and evaporation temperature set for the rotary evaporator. The method was validated for 3 concentration levels for both PTSO (100, 500, 1000 ng g-1) and PTS (500, 1150, 2300 ng g-1). The highest recoveries of PTSO and PTS were obtained using 12.5 mL of 100% acetonitrile, stirring for 15 min, and an evaporation temperature of 20 °C. The validated method was further applied to detect and quantify these compounds in different feed matrices. In conclusion, this is the first study to simultaneously analyze PTSO and PTS at low concentrations, employing a sensitive technique such as UPLC-MS/MS.
Assuntos
Ração Animal/análise , Ácidos Tiossulfônicos/análise , Allium/química , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Espectrometria de Massas em TandemRESUMO
Garlic contains a wide range of organosulfur compounds, which exhibit a broad spectrum of biological activities. Amongst the sulfur-containing compounds in garlic, the thiosulfonates are considerably popular in various fields. In light of this, we decided to investigate the enzyme inhibition ability of thiosulfonates. In this paper, the synthesis and biological activity of a small library of unsymmetrical thiosulfonates as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are described. The activity evaluation revealed nanomolar IC50 and Ki values against both enzymes tested. Furthermore, molecular docking studies allowed for the determination of possible binding interactions between the thiosulfonates and AChE.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Alho/química , Fármacos Neuroprotetores/farmacologia , Ácidos Tiossulfônicos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Ácidos Tiossulfônicos/síntese química , Ácidos Tiossulfônicos/químicaRESUMO
Diaryl disulfides and diaryl thiosulfonates were synthesized with the two phenyl rings of all compounds bearing identical halide substituents. Because of structural similarity to the potent antimitotic natural product combretastatin A-4 (CA-4), the compounds were examined for inhibition of tubulin polymerization, and the thiosulfonates were more active than the disulfides. The nine thiosulfonates had IC50 values ranging from 1.2 to 9.1 µM, as compared with 1.3 µM obtained with CA-4. The compounds thus ranged from equipotent with CA-4 to 7-fold less active. The nine disulfides had IC50 values ranging from 1.2 to 5.1 µM, as compared with 0.54 µM obtained with CA-4. The compounds thus ranged from less than half as active as CA-4 to over 9-fold less active. The most active members of each group, 2 g and 3c, in the assembly assay were modeled into the colchicine site. Compound 3c had significant hydrophobic interactions with ß-tubulin residues CYS 241 and ALA 250, and its thiosulfonate bridge made a hydrogen bond with ß-tubulin residue ASN 258. Compound 2 g had hydrophobic interactions with ß-tubulin residues ALA 250, CYS 241 and ALA 254, but there was no significant interaction of the disulfide bridge with tubulin.
Assuntos
Bibenzilas/química , Proliferação de Células/efeitos dos fármacos , Dissulfetos/síntese química , Dissulfetos/farmacologia , Ácidos Tiossulfônicos/síntese química , Ácidos Tiossulfônicos/farmacologia , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Dissulfetos/química , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Ácidos Tiossulfônicos/químicaRESUMO
In this work, we sought to investigate the effects of a thiosulfinate-enriched garlic extract, co-administered with 5-fluorouracil (5-FU) or oxaliplatin chemotherapy, on the viability of colon cancer cells (Caco-2 and HT-29). We also addressed the economic feasibility of a new combined treatment of this thiosulfinate-enriched garlic extract, with oxaliplatin that could reduce the dosage and costs of a monotherapy. The thiosulfinate-enriched garlic extract not only enhanced the impact of 5-FU and oxaliplatin (500 µM) in decreasing Caco-2 and HT-29 viability, but also showed a higher effect than standard 5-FU and oxaliplatin chemotherapy as anti-cancer agents. These results provided evidences for the combination of lyophilized garlic extract and 5-FU or oxaliplatin as a novel chemotherapy regimen in colon cancer cells that may also reduce the clinical therapy costs.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Análise Custo-Benefício , Alho/química , Extratos Vegetais/química , Ácidos Tiossulfônicos/química , Antineoplásicos/economia , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fluoruracila/farmacologia , Alho/metabolismo , Células HT29 , Humanos , Oxaliplatina/farmacologia , Extratos Vegetais/farmacologiaRESUMO
The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27-30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds.
Assuntos
Inibidores de Cisteína Proteinase/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Ácidos Tiossulfônicos/uso terapêutico , Animais , Inibidores de Cisteína Proteinase/farmacologia , Relação Estrutura-Atividade , Ácidos Tiossulfônicos/farmacologiaRESUMO
ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Two-fold intraperitoneal injections of doxorubicin in a cumulative dose of 8 mg/kg were followed by inhibition of tumor growth by 49.5%. Combined treatment with TS-13 and doxorubicin suppressed the tumor growth by 55.4%. In contrast to doxorubicin, TS-13 inhibited NO generation by peritoneal macrophages. The results show the prospect of studying TS-13 in the context of overcoming drug-resistance of tumors.
Assuntos
Antioxidantes/farmacologia , Doxorrubicina/farmacologia , Fenóis/farmacologia , Ácidos Tiossulfônicos/farmacologia , Animais , Carcinoma Pulmonar de Lewis/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
SCOPE: Propyl-propane thiosulfonate (PTSO) is a component isolated from garlic (Allium sativum) with antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial properties. In consequence, PTSO can be a potential candidate for the treatment of inflammatory bowel diseases. METHODS AND RESULTS: The anti-inflammatory effects of PTSO are studied in two mice models of colitis: 2,4-dinitrobenzene sulfonic acid (DNBS) (PTSO doses: 0.01-10 mg kg-1 ) and dextran sodium sulfate (DSS) (PTSO doses: 0.01-0.1 mg kg-1 ). The immunomodulatory effects of PTSO (0.1-25 µm) are also shown in vitro in Caco-2 and THP-1 cells, reducing the production of pro-inflammatory mediators and downregulating mitogen-activated protein kinases (MAPKs) signaling pathways. This compound displays beneficial effects in both models of mouse colitis by reducing the expression of different pro-inflammatory mediators and improving the intestinal epithelial barrier integrity. Moreover, PTSO ameliorates the altered gut microbiota composition observed in DSS colitic mice. CONCLUSION: PTSO exerts intestinal anti-inflammatory activity in experimental colitis in mice. This anti-inflammatory activity can be associated with the immunomodulatory properties of PTSO through the regulation of the activity of cells involved in the inflammatory response. Furthermore, PTSO is able to restore the intestinal epithelial barrier function and to ameliorate the intestinal microbiota homeostasis, thus supporting its future development in human IBD.
Assuntos
Alcanossulfonatos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Colite/tratamento farmacológico , Fatores Imunológicos/farmacologia , Ácidos Tiossulfônicos/farmacologia , Animais , Células CACO-2 , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana , Dinitrofluorbenzeno/análogos & derivados , Modelos Animais de Doenças , Alho/química , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos EndogâmicosRESUMO
Glycosyl phenylthiosulfonates are reagents which are valuable for the S-glycosylation decoration of organic compounds and proteins. Here, one-pot multiple-component synthesis of glycosyl phenylthiosulfonates from sulfinate, sulfur powder and glycosyl bromides is reported. The reactions afford glycosyl phenylthiosulfonates in good yields under mild conditions. Further application and exploration of glycosyl phenylthiosulfonates are still on underway in our group.
Assuntos
Brometos/química , Ácidos Sulfínicos/química , Ácidos Tiossulfônicos/síntese química , Técnicas de Química Sintética , Glicosilação , Estrutura Molecular , Enxofre/química , Ácidos Tiossulfônicos/químicaRESUMO
BACKGROUND: The aim of this study was to compare the in vitro antibacterial activity of two compounds derived from Alliaceae, PTS (propyl-propane-thiosulfinate), and PTSO (propyl-propane-thiosulfonate), with that of other antibiotics commonly used against bacteria isolated from humans. MATERIALS AND METHODS: A total of 212 gram-negative bacilli and 267 gram-positive cocci isolated from human clinical samples and resistant to at least one group of antibiotics were selected. In order to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) to various antibiotics as well as PTS and PTSO, all isolates underwent broth microdilution assay. RESULTS: PTS showed moderate activity against Enterobacteriaceae with MIC50 (and MBC50) and MIC90 (and MBC90) values of 256-512 mg/L, while PTSO showed greater activity with MIC50 and MIC90 values of 64-128 mg/L and MBC50 and MBC90 values of 128-512 mg/L. These data show the bactericidal activity of both compounds and indicate that PTSO was more active than PTS against this group of bacteria. Both compounds showed lower activity against P. aeruginosa (MIC50 = 1024 mg/L, MIC90 = 2048 mg/L, MBC50 = 2048 mg/L, and MBC90 = 2048 mg/L, for PTS; MIC50 = 512 mg/L, MIC90 = 1024 mg/L, MBC50 = 512 mg/L, and MBC90 = 2048 mg/L, for PTSO) compared to those obtained in others nonfermenting gram-negative bacilli (MIC50 = 128 mg/L, MIC90 = 512 mg/L, MBC50 = 128 mg/L, and MBC90 = 512 mg/L, for PTS; MIC50 = 64 mg/L, MIC90 = 256 mg/L, MBC50 = 64 mg/L, and MBC90 = 256 mg/L, for PTSO) and also indicate the bactericidal activity of both compounds against these groups of bacteria. Finally, the activity against S. aureus, E. faecalis, and S. agalactiae was higher than that observed against enterobacteria, especially in the case of PTSO (MIC50 = 8 mg/L, MIC90 = 8 mg/L, MBC50 = 32 mg/L, and MBC90 = 64 mg/L, in S. aureus; MIC50 = 4 mg/L, MIC90 = 8 mg/L, MBC50 = 8 mg/L, and MBC90 = 16 mg/L, in E. faecalis and S. agalactiae). CONCLUSION: PTS and PTSO have a significant broad spectrum antibacterial activity against multiresistant bacteria isolated from human clinical samples. Preliminary results in present work provide basic and useful information for development and potential use of these compounds in the treatment of human infections.
Assuntos
Allium/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Ácidos Tiossulfônicos/farmacologia , Bactérias/isolamento & purificação , Infecções Bacterianas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Propano/químicaRESUMO
Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with broad antimicrobial activities in the low µM range against Gram-positive and -negative bacteria, including antibiotic resistant strains, and fungi. Allicin reacts with thiol groups and can inactivate essential enzymes. However, allicin is unstable at room temperature and antimicrobial activity is lost within minutes upon heating to >80 °C. Allicin's antimicrobial activity is due to the thiosulfinate group, so we synthesized a series of allicin analogues and tested their antimicrobial properties and thermal stability. Dimethyl-, diethyl-, diallyl-, dipropyl- and dibenzyl-thiosulfinates were synthesized and tested in vitro against bacteria and the model fungus Saccharomyces cerevisiae, human and plant cells in culture and Arabidopsis root growth. The more volatile compounds showed significant antimicrobial properties via the gas phase. A chemogenetic screen with selected yeast mutants showed that the mode of action of the analogues was similar to that of allicin and that the glutathione pool and glutathione metabolism were of central importance for resistance against them. Thiosulfinates differed in their effectivity against specific organisms and some were thermally more stable than allicin. These analogues could be suitable for applications in medicine and agriculture either singly or in combination with other antimicrobials.
Assuntos
Arabidopsis/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/microbiologia , Bactérias/patogenicidade , Dissulfetos , Fungos/patogenicidade , Alho/química , Glutationa/metabolismo , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Ácidos Sulfínicos/química , Ácidos Tiossulfônicos/química , Ácidos Tiossulfônicos/farmacologiaRESUMO
Alzheimer's disease (AD) is characterized by the presence of tau filaments in the brain whose structure was recently solved. The formation of AD filaments is routinely modeled in vitro by mixing tau with heparin. This study shows that heparin-induced tau filaments are markedly different from the AD filaments and are highly heterogeneous.
Assuntos
Doença de Alzheimer/patologia , Heparina/metabolismo , Proteínas de Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Sequência de Aminoácidos , Amiloide/química , Amiloide/metabolismo , Heparina/química , Humanos , Proteínas de Membrana/química , Estrutura Molecular , Fragmentos de Peptídeos/química , Agregação Patológica de Proteínas/metabolismo , Ligação Proteica , Estrutura Quaternária de Proteína/efeitos dos fármacos , Pirrolidinas/química , Marcadores de Spin , Ácidos Tiossulfônicos/químicaRESUMO
Tert-butylhydroquinone (tBHQ) is a highly effective phenolic antioxidant used in edible oils and fats in foods as well as in medicines and cosmetics. TBHQ has been shown to have both chemoprotective and carcinogenic effects. Furthermore, it has potential anti-inflammatory, antiatherogenic, and neuroprotective activities. TBHQ induces phase II detoxification enzymes via the Keap1/Nrf2/ARE mechanism, which contributes to its chemopreventive functions. Nonetheless, there is growing evidence that biological effects of tBHQ may be mediated by Nrf2-independent mechanisms related to various signaling cascades. Here, we studied changes in gene expression of phase I, II, and III drug metabolizing enzymes/transporters as well as protein levels and activities of cytochromes P450 (CYPs) elicited by tBHQ and its structural homolog TS-13 in the mouse liver. Next, we carried out gene expression analysis to identify signal transduction pathways modulated by the antioxidants. Mice received 100 mg/kg tBHQ or TS-13 per day or only vehicle. The liver was collected at 12 hours and after 7 days of the treatment. Protein and total RNA were extracted. Gene expression was analyzed using Mouse Drug Metabolism and Signal Transduction PathwayFinder RT2Profiler™PCR Arrays. A western blot analysis was used to measure protein levels and a fluorometric assay was employed to study activities of CYPs. Genes that were affected more than 1.5-fold by tBHQ or TS-13 treatment compared with vehicle were identified. Analysis of the gene expression data revealed changes in various genes that are important for drug metabolism, cellular defense mechanisms, inflammation, apoptosis, and cell cycle regulation. Novel target genes were identified, including xenobiotic metabolism genes encoding CYPs, phase II/III drug metabolizing enzymes/transporters. For Cyp1a2 and Cyp2b, we observed an increase in protein levels and activities during tBHQ or TS-13 treatment. Changes were found in the gene expression regulated by NFκB, androgen, retinoic acid, PI3K/AKT, Wnt, Hedgehog and other pathways.
Assuntos
Hidroquinonas/farmacologia , Fígado/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ácidos Tiossulfônicos/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Western Blotting , Sistema Enzimático do Citocromo P-450/metabolismo , Inativação Metabólica/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Pyridoxal 5'-phosphate-dependent methionine γ-lyase (MGL) catalyzes the ß-elimination reaction of S-alk(en)yl-l-cysteine sulfoxides to thiosulfinates, which possess antimicrobial activity. Partial inactivation of the enzyme in the course of the reaction occurs due to oxidation of active site cysteine 115 conserved in bacterial MGLs. In this work, the C115H mutant form of Clostridium sporogenes MGL was prepared and the steady-state kinetic parameters of the enzyme were determined. The substitution results in an increase in the catalytic efficiency of the mutant form towards S-substituted l-cysteine sulfoxides compared to the wild type enzyme. We used a sulfoxide/enzyme system to generate antibacterial activity in situ. Two-component systems composed of the mutant enzyme and three S-substituted l-cysteine sulfoxides were demonstrated to be effective against Gram-positive and Gram-negative bacteria and three clinical isolates from mice. © 2016 IUBMB Life, 68(10):830-835, 2016.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/química , Liases de Carbono-Enxofre/química , Cisteína/análogos & derivados , Cisteína/química , Ácidos Tiossulfônicos/síntese química , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Biocatálise , Liases de Carbono-Enxofre/genética , Clostridium/enzimologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Cinética , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Sulfóxidos/química , Ácidos Tiossulfônicos/farmacologiaRESUMO
BACKGROUND: Garlic has been used for centuries in folk medicine for its health promoting and cancer preventative properties. The bioactive principles in crushed garlic are allyl sulphur compounds which are proposed to chemically react through (i) protein S-thiolation and (ii) production of ROS. METHODS: A collection of R-propyl disulphide and R-thiosulfonate compounds were synthesised to probe the importance of thiolysis and ROS generation in the cytotoxicity of garlic-related compounds in WHCO1 oesophageal cancer cells. RESULTS: A significant correlation (R(2)=0.78, Fcrit (7,1) α=0.005) was found between the cytotoxicity IC(50) and the leaving group pK(a) of the R-propyl disulphides and thiosulfonates, supporting a mechanism that relies on the thermodynamics of a mixed disulphide exchange reaction. Disulphide (1) and thiosulfonate (11) were further evaluated mechanistically and found to induce G(2)/M cell-cycle arrest and apoptosis, inhibit cell proliferation, and generate ROS. When the ROS produced by 1 and 11 were quenched with Trolox, ascorbic acid or N-acetyl cysteine (NAC), only NAC was found to counter the cytotoxicity of both compounds. However, NAC was found to chemically react with 11 through mixed disulphide formation, providing an explanation for this apparent inhibitory result. CONCLUSION: Cellular S-thiolation by garlic related disulphides appears to be the cause of cytotoxicity in WHCO1 cells. Generation of ROS appears to only play a secondary role. GENERAL SIGNIFICANCE: Our findings do not support ROS production causing the cytotoxicity of garlic-related disulphides in WHCO1 cells. Importantly, it was found that the popular ROS inhibitor NAC interferes with the assay.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Dissulfetos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Alho , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Ácidos Tiossulfônicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/síntese química , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Ácidos Tiossulfônicos/síntese química , Fatores de TempoRESUMO
An efficient deborylthiolation of aryl- and alkenylborons with thiosulfonates has been achieved under mild conditions using a copper catalyst. All steps of the experimental process were free from unpleasant odors. The mild reaction conditions as well as ready availability of boron compounds and thiosulfonates enabled easy access to an array of sulfides, including those bearing sensitive functional groups.
Assuntos
Compostos de Boro/química , Cobre/química , Sulfetos/química , Sulfetos/síntese química , Ácidos Tiossulfônicos/química , Catálise , Estrutura MolecularRESUMO
The first thiol-specific turn-on probe, BODIPY-TS, utilizing a thiosulfonate scaffold as the thiol recognition unit was reported. BODIPY-TS displays low toxicity, and features high sensitivity, fast response and quantitative reaction towards thiols. The structural novelty of BODIPY-TS would guide the development of novel thiol probes.
Assuntos
Compostos de Sulfidrila/química , Ácidos Tiossulfônicos/análise , Compostos de Sulfidrila/análiseRESUMO
The ban on the use of antibiotics as growth promoters in animal feeds in the European Union has stimulated research on potential alternatives. Recently, propyl-propane thiosulfonate (PTSO), a stable organosulfurate compound of garlic, was purified. The objectives of the current study were to investigate the potential effects of PTSO on rumen microbial fermentation and to define effective doses. Two experiments were conducted using dual-flow continuous culture fermenters in 2 replicated periods. Each experimental period consisted of 5 d for adaptation of the ruminal fluid and 3 d for sampling. Temperature (39°C), pH (6.4), and liquid (0.10 h(-1)) and solid (0.05 h(-1)) dilution rates were maintained constant. Samples were taken 2 h after feeding and from the 24-h effluent. Samples were analyzed for volatile fatty acids (VFA) and nitrogen fractions, and degradation of nutrients was calculated. In addition, 24-h effluents from experiment 2 were analyzed for their fatty acid (FA) profile. Treatments in experiment 1 included a negative control without additive, a positive control with monensin (12mg/L), and PTSO at 30 and 300mg/L. The addition of 30mg/L did not affect any of the measurements tested. The addition of 300mg/L reduced microbial fermentation, as suggested by the decreased total VFA concentration, true degradation of organic matter and acid detergent fiber, and a tendency to decrease neutral detergent fiber degradation. Experiment 2 was conducted to test increasing doses of PTSO (0, 50, 100, and 150mg/L) on rumen microbial fermentation. At 2 h postfeeding, total VFA and molar proportion of propionate responded quadratically, with higher values in the intermediate doses. Molar proportions of butyrate increased and branched-chain VFA decreased linearly as the dose of PTSO increased. In the 24-h effluents, total VFA, acetate, and branched-chain VFA concentrations decreased linearly and those of propionate responded cubically with the highest value at 100mg/L. Saturated FA decreased and unsaturated FA increased linearly with increasing dose of PTSO. The concentration of trans-10,cis-12 conjugated linoleic acid decreased by 78.5% with addition of PTSO at the highest dose (150mg/L). Results suggest the potential of PTSO to modify ruminal fermentation in a direction consistent with higher propionate molar proportion, higher outflow of unsaturated FA, and low trans-10,cis-12 conjugated linoleic acid in an effective dose between 50 and 100mg/L.
Assuntos
Compostos Alílicos/química , Bovinos/metabolismo , Fermentação/efeitos dos fármacos , Rúmen/microbiologia , Sulfetos/química , Ácidos Tiossulfônicos/farmacologia , Acetatos/análise , Ração Animal , Animais , Reatores Biológicos , Líquidos Corporais/metabolismo , Butiratos/análise , Dieta , Fibras na Dieta/metabolismo , Ácidos Graxos/análise , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Concentração de Íons de Hidrogênio , Propionatos/análise , Rúmen/metabolismoRESUMO
Effects of water-soluble phenolic antioxidant sodium 3-(3'-tret-butyl-4'-hydroxyphenyl)-propyl thiosulfonate (TS-13), potassium 3,5-dimethyl-4-hydroxybenzyl thioetanoate (BEP-11-K) and potassium 3-(3',5'-ditretbutyl-4'-hydroxyphenyl)-propionate (potassium phenosan) on tumor cells proliferative activity and the role of redox-dependent and calcium-dependent signaling mechanisms in realization of tumor cell response to the antioxidant action were studied. Potassium phenosan and BEP-11-K were found to stimulate proliferation and ARE-inducing phenolic antioxidant TS-13 was found to inhibit tumor cell growth in culture. The tumor cell growth rate depended on the rate of intracellular reactive oxygen species production and was decreased by apocynin (a NADPH-oxidase inhibitor) and antimycin A (an ubiquinol-cytochrome c oxidoreductase inhibitor). TS-13 action on tumor cells was accompanied by a transient increase in intracellular reactive oxygen species production and the intracellular calcium concentration, whereas cell incubation with potassium phenosan and BEP-11-K did not influence the reactive oxygen species level and intracellular calcium ions. Cyclosporine A blocked the inhibitory effect of TS-13. Thus, it can be reasonably speculated that phenolic antioxidant TS-13 starts mitochondria-dependent apoptosis in tumor cells by the opening of permeability transition pores.