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European Journal of Medicinal Chemistry Jul 2010A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent....
A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent. Water-soluble analogs of anethole trithione were synthesized via substituting the methyl group of anethole trithione with the simple hydrophilic alkylamino group, and subjected to physiochemical, pharmacological and metabolic studies. The prodrugs displayed increased solubility as well as other physiochemical properties favorable for parenteral use. Among the analogs synthesized, the compound 5a exhibited best hepatoprotective activity at the dose of 2.0 mg/kg in mice equal to that of anethole trithione. The in vivo metabolic investigation demonstrated that the straight-side chain prodrug 5a could convert to desmethyl anethole trithione in vivo, while the ring-side chain prodrug 5d could not. The hepatoprotective activity of the prodrugs might result from the active metabolite desmethyl anethole trithione.
Topics: Anethole Trithione; Animals; Drug Design; Drug Stability; Hydrophobic and Hydrophilic Interactions; Liver; Male; Mice; Prodrugs; Solubility; Water
PubMed: 20392547
DOI: 10.1016/j.ejmech.2010.03.029 -
Free Radical Biology & Medicine May 2010The H(2)S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but...
The H(2)S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but it seems to spare the gastric mucosa by affecting redox imbalance through increased H(2)S/glutathione (GSH) formation. Nevertheless, the mechanisms by which ACS14 is able to elevate the levels of these agents has not been fully elucidated so far. In this manuscript the effect of an acute ip administration of ACS14 and of its dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, ADTOH) on the overall thiol content of rat tissues and on the main enzymes involved in the maintenance of thiol homeostasis is reported. ACS14 and ADTOH treatments were shown to induce a significant increase not only of GSH but also of cysteine in plasma and in several rat tissues as well as of H(2)S plasma levels. Conversely, a significant decrease of homocysteine in most rat organs and in plasma was observed. Most of these phenomena are supposed to be linked to the elevated intracellular levels of cysteine induced by treatments with either ACS14 or ADTOH.
Topics: Anethole Trithione; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chromatography, High Pressure Liquid; Glutathione; Homeostasis; Hydrogen Sulfide; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds
PubMed: 20171274
DOI: 10.1016/j.freeradbiomed.2010.02.014 -
[Zhonghua Yan Ke Za Zhi] Chinese... Jun 2009To investigate anethol trithione therapic efficiency on dry eye. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate anethol trithione therapic efficiency on dry eye.
METHODS
It was a prospective random double-blind controlled study. Eighty cases diagnosed dry eye in Ocular Surface Out-patient Clinic of Xiamen University Affiliated Xiamen Eye Center from 2006 to 2008 were divided into two groups: anethol trithione group and control group, 40 cases in each group. Every group was then divided into two subgroups: weak dry eye subgroup,middle and severe dry eye subgroup. All groups had been added with 0.05% refresh drops. All patients had been detected and evaluated by subjective symptoms of dry eye, visual acuity, corneal fluorescent staining (F1), break-up time (BUT) and Schirmer I test (SIT) at pretherapy and 3, 7, 28 d of post-therapy. All groups had been compared and analyzed by F test and sample mean difference (SMD) or median difference (MD) comparison between pre-therapy and post-therapy.
RESULTS
Except of tear and red eye,the other subjective symptoms of dry eye, Fl, BUT and SIT of weak dry eye subgroup of both groups had been improved at 7 d after therapy. Only those of middle and severe dry eye subgroup of anethol trithione group had been improved at 7 d after therapy compared with those of pretherapy: SMD = 0.96 (visual tiredness), 1.26 (dry and unsmooth sensation), 0.82 (foreign body sensation), 1.28 (burning sensation), 1.05 ( photophobia), 1.48 (pain); MD = 0.30 (visual acuity), 4.00 (Fl), 5.00 (BUT), 5.00 (SIT) [F = 15.30 (visual tiredness), 15.68 (dry and unsmooth sensation), 13.56 (foreign body sensation), 20.91 (burning sensation), 18.90 (photophobia), 27.22 (pain), 10.54 (visual acuity),188.21 (F1), 261.76 (BUT), 269.05 (SIT); P < 0.05]. Those of middle and severe dry eye subgroup of control group hadn't significantly been improved at 28 d after therapy: SMD = 0.10 (visual tiredness), 0.16 (dry and unsmooth sensation), 0.09 (foreign body sensation), 0.38 (burning sensation), 0.24 (photophobia), 0.36 (pain), 0.23 (red eye); MD = 0.10 (visual acuity), 0.50 (Fl), 0.50 (BUT), 0.50 (SIT) [F = 1.76 (visual tiredness), 1.61 (dry and unsmooth sensation), 1.02 (foreign body sensation), 2.39 (burning sensation), 2.42 (photophobia), 2.73 (pain), 2.55 (red eye), 1.46 (visual acuity), 2.35 (Fl), 2.90 (BUT), 2.76 (SIT); P > 0.05]. SIT of anethol trithione group had been improved more significantly after therapy (F = 13.77, P < 0.05).
CONCLUSION
Anethol trithione could significantly improve middle and severe dry eye patients' symptoms and signs whose lacrimal gland function survival and it has clinical application value.
Topics: Adult; Anethole Trithione; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Treatment Outcome; Xerophthalmia
PubMed: 19957670
DOI: No ID Found -
Lung Cancer (Amsterdam, Netherlands) May 2010The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and...
The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 microg/ml concentrations significantly reduced prostaglandin (PG)E(2) levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 microg/ml, respectively. Using the MTT assay, 10 microg/ml S-valproate, NO-aspirin and Cay10404, a selective COX-2 inhibitor, but not SC-560, a selective COX-1 inhibitor, inhibited the growth of A549 cells. In vivo, 18mg/kg i.p. of S-valproate and S-diclofenac, but not S-sulindac, significantly inhibited A549 or NCI-H1299 xenograft proliferation in nude mice, but had no effect on the nude mouse body weight. The mechanism by which S-valproate and S-diclofenac inhibited the growth of NSCLC cells was investigated. Nitric oxide-aspirin but not S-valproate caused apoptosis of NSCLC cells. By Western blot, S-valproate and S-diclofenac increased E-cadherin but reduced vimentin and ZEB1 (a transcriptional suppressor of E-cadherin) protein expression in NSCLC cells. Because S-valproate and S-diclofenac inhibit the growth of NSCLC cells and reduce PGE(2) levels, they may prove beneficial in the chemoprevention and/or therapy of NSCLC.
Topics: Anethole Trithione; Animals; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Pyrazoles; Sulfones; Valproic Acid
PubMed: 19628293
DOI: 10.1016/j.lungcan.2009.06.012 -
International Journal of Pharmaceutics Sep 2009This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared... (Comparative Study)
Comparative Study
This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared the performance of different formulations. Two groups of lipid-based formulations, sub-microemulsion (SME) and oil solution, were prepared using short (SCT), medium (MCT) and long (LCT) chain triglycerides respectively; aqueous suspension was used as the reference formulation. In vitro and in vivo studies were conducted to investigate the impact of lipid composition and formulation on drug absorption. In vitro digestion was used to analyze lipid digestion rates and drug distribution/solubilization. After in vitro digestion, the performance rank order for drug solubilization was SCT
Topics: Administration, Oral; Anethole Trithione; Animals; Biological Availability; Chemistry, Pharmaceutical; Emulsions; Intestinal Absorption; Male; Rats; Rats, Sprague-Dawley; Solubility; Triglycerides
PubMed: 19508887
DOI: 10.1016/j.ijpharm.2009.06.001 -
Journal of Pharmaceutical and... Jul 2008A simple, selective and reproducible high-performance liquid chromatographic (HPLC) method via enzymatic hydrolysis of glucuronide conjugates of 4-hydroxy-anethole...
A simple, selective and reproducible high-performance liquid chromatographic (HPLC) method via enzymatic hydrolysis of glucuronide conjugates of 4-hydroxy-anethole trithione (ATX) was established for simultaneous determination of ATX. Human plasma samples were hydrolyzed by beta-glucuronidase and followed by subsequent extraction with cyclohexane-isopropanol (95:5, v/v) using mifepristone as the internal standard. Chromatography was carried out on a reverse phase C(18) column (250 mm x 4.6 mm, 5 microm) and kept at 30 degrees C, with UV detection set at 346 nm. The mobile phase consisted of a mixture of methanol and water (75:25, v/v), at a flow rate of 1 ml/min. It was validated and proved to be linear in the range of 20-1500 ng/ml, with the regression equation Y = 0.0016C-0.0069, r=0.9992. And the limit of quantification (LOQ) concentration in plasma was 20 ng/ml. The absolute recoveries of ATX at three concentrations were 32.04, 38.95 and 44.06% and the relative recoveries were 104.80, 102.53 and 107.04%, which showed that the analytical method was sensible, accurate and reproducible. The method was utilized on a double-blind, randomized, single dose, two period, and crossover bioequivalence study of ATT tablets produced by different companies in 20 healthy male Chinese subjects, with a washout between every two periods. Blood samples were collected over each period of 10h and various pharmacokinetic parameters were determined. Natural log-transformed values were compared by analysis of variance followed by classical 90% confidence interval for C(max), AUC(0-t) and AUC(0-infinity) and was found to be within the range, which indicated that the two products were bioequivalence.
Topics: Anethole Trithione; Area Under Curve; Chromatography, High Pressure Liquid; Drug Stability; Glucuronidase; Humans; Hydrolysis; Therapeutic Equivalency
PubMed: 18353592
DOI: 10.1016/j.jpba.2008.01.044 -
Bioorganic & Medicinal Chemistry Letters Mar 2008One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The...
One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory activity is described for dithiolethiones and thiosulfonates.
Topics: Acetylation; Adenocarcinoma; Apoptosis; Blotting, Western; Cell Proliferation; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship; Thiosulfonic Acids; Tumor Cells, Cultured; Valproic Acid
PubMed: 18294844
DOI: 10.1016/j.bmcl.2008.02.007 -
Analytica Chimica Acta Jul 2007A rapid, sensitive and reliable high performance liquid chromatographic method coupled with tandem mass spectrometry via electrospray ionization (ESI) source... (Clinical Trial)
Clinical Trial
A rapid, sensitive and reliable high performance liquid chromatographic method coupled with tandem mass spectrometry via electrospray ionization (ESI) source (HPLC-MS/MS) has been developed and validated for the determination of anethole trithione (ATT) in human plasma. Diazepam was employed as the internal standard (IS). Sample extracts following liquid-liquid extraction were injected into the HPLC-MS/MS system. The analyte and IS were eluted isocratically on a C18 column, with a mobile phase consisting of methanol and aqueous ammonium acetate solution (5 mM) (80:20, v/v) . The ions were detected by a triple quadrupole mass spectrometric detector in the positive mode. Quantification was performed using selected reaction monitoring (SRM) of the transitions m/z 240.88-->197.91 and m/z 285.01-->193.02 for ATT and for the IS, respectively. The analysis time for each run was 5.0 min. The calibration curve fitted well over the concentration range of 0.02-5 ng mL(-1), with the regression equation y = 1.1014x + 0.0003631, r = 0.9992. The intra-batch and inter-batch R.S.D.% were less than 15% at all concentration levels within the calibration range. The recoveries were more than 80%. The present method provides a modern, rapid and robust procedure for the pharmacokinetic study of ATT. Some important pharmacokinetic parameters of ATT in healthy Chinese volunteers are also given for the first time.
Topics: Adult; Anethole Trithione; Chromatography, High Pressure Liquid; Humans; Male; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 17586125
DOI: 10.1016/j.aca.2007.05.038 -
Life Sciences Jun 2007Decreases in the 26S proteasome are related to the toxicities of abnormal protein aggregates and may contribute to pathogenesis of degenerative diseases. Therefore,... (Comparative Study)
Comparative Study
Tissue specific increase of the catalytic subunits of the 26S proteasome by indirect antioxidant dithiolethione in mice: enhanced activity for degradation of abnormal protein.
Decreases in the 26S proteasome are related to the toxicities of abnormal protein aggregates and may contribute to pathogenesis of degenerative diseases. Therefore, maintenance of proteasome function can be a novel strategy to protect cells against abnormal protein-mediated toxicity. In the present study, we have demonstrated the tissue specific increase of the catalytic subunits of the proteasome in mice following oral administration of 3H-1,2-dithiole-3-thione (D3T, 0.5 mmol/kg), which functions as a cancer preventive agent in animal and human studies. Expression of the 20S catalytic core subunits PSMB5, PSMB6, and PSMB7 were increased in liver, lung, small intestine, and colon of mice at 24 h after D3T treatment. Elevated expression of proteasome catalytic subunits led to increases in proteasomal peptidase activities in these tissues. Oral administration of D3T also exerted a pharmacodynamic action in some brain regions of these mice and proteasomal peptidase activities were significantly elevated in the cerebral cortex-hippocampus. Moreover, tissue extracts from D3T-treated mice and cell lysates obtained from D3T-incubated murine neuroblastoma cells exhibited the enhanced capacity to degrade mutant human SOD1G93A protein. These results indicate that the catalytic subunits of the 26S proteasome are inducible in multiple tissues of mouse including brain by exogenous chemical treatment. Increased proteasome expression by inducers may have a role in protection/attenuation of protein aggregate-mediated disorders.
Topics: Analysis of Variance; Anethole Trithione; Animals; Brain; Catalytic Domain; DNA Primers; Escherichia coli; Female; Gene Expression Regulation, Enzymologic; Immunoblotting; Mice; Mice, Inbred ICR; NAD(P)H Dehydrogenase (Quinone); NADPH Dehydrogenase; Proteasome Endopeptidase Complex; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase
PubMed: 17521679
DOI: 10.1016/j.lfs.2007.04.014 -
British Journal of Pharmacology May 2007Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase...
BACKGROUND AND PURPOSE
Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti-angiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate.
EXPERIMENTAL APPROACH
Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.
KEY RESULTS
Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser(78) phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H(2)S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity.
CONCLUSIONS AND IMPLICATION
S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.
Topics: Anethole Trithione; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Endothelial Cells; HSP27 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Mice; Mice, Inbred C57BL; Phosphorylation; Solubility; Valproic Acid; Zebrafish
PubMed: 17351657
DOI: 10.1038/sj.bjp.0707198