Studies on the metabolism of 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rats by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.
ABSTRACT 4-Methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride(TM208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. In this study, the metabolism of TM208 in rats was studied for the first time by high-performance liquid chromatography coupled with tandem mass spectrometry. Following a single oral administration to rats, TM208 was metabolized to eight metabolites (M1-M8). M1 is the desmethyl metabolite and the acylation of M1 with N-acetyl transferase results in M6 (N-acetyl metabolite), M5 is N-formyl metabolite; M4 is phenyl monohydroxylation metabolite, M2 is the sulfine metabolite of TM208, and M3 is also an odd-oxygen added products which the possible oxidation site has described in this paper; M8 is the metabolite resulting from the replacement of '-C=S' with '-C=O', M7 is a ring-opened piperazine oxidation products to a kind of acid.
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ABSTRACT: TM208 and TM209, dithiocarbamate derivatives with potential anti-cancer effects, were evaluated in reversible and time-dependent cytochrome P450 (CYP) 3A inhibition assays in rat liver microsomes using testosterone as probe substrate. Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A. For reversible inhibition on rat CYP3A, the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM, respectively. For time-dependent inhibition, the inactivation constants (Kl) were 31.93±12.64 and 32.91±15.58 μM, respectively, and the maximum inactivation rates (kinact) were 0.03497±0.0069 and 0.07259±0.0172 min−1 respectively. These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209.04/2012; 2(2):181–187. DOI:10.1016/j.apsb.2012.02.006
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ABSTRACT: Aim:To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacokinetic characteristics of TM208 in human breast cancer xenograft mice.Methods:Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell proliferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg·kg(-1)·d(-1)) or tamoxifen (50 mg·kg(-1)·d(-1)) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS.Results:Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC50 values were 36.38±3.77 and 18.13±0.76 μmol/L, respectively). TM208 (20-150μmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-dependently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor.Conclusion:Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.Acta Pharmacologica Sinica 12/2013; DOI:10.1038/aps.2013.156 · 2.50 Impact Factor
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ABSTRACT: 4-Methylpiperazine-1-carbodithiocacid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208) was a potential antitumor new drug with many preliminary studies in pharmacokinetics and pharmacodynamics. This study aims to determine whether TM208 elicits toxic effects by metabonomics for the first time. Sprague Dawley (SD) rats were exposured to TM208 at a single therapeutic dose (100mg/kg/d) for 5 days, metabolites of urine samples from both control and TM208-treated groups were analyzed using high performance liquid chromatography-electrospray ionization source in combination with hybrid ion trap and high-resolution time-of-flight mass spectrometry (HPLC-ESI-IT-TOF/MS). Metabolites such as aminoadipic acid, creatine, gluconic acid, cis-aconitic acid, succinic acid and pipecolic acid which changed significantly, were identified as potential biomarkers. These results suggest that the changes in urinary metabolites of rats after exposure to TM208 were mainly related to energy metabolism and amino acid metabolism, which may be helpful to further understand the mechanism of TM208 toxicity in rats and a new drug development.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 04/2014; 959C:49-54. DOI:10.1016/j.jchromb.2014.03.036 · 2.69 Impact Factor