Direct synthesis of 5-azapyrimidine 2′-deoxyribonucleosides. Hydrolysis of 5-aza-2′-deoxycytidine

Pískala, A.; Synáčková, M.; Tománková, Hana; Fiedler, Pavel; Žižkovský, Václav

doi:10.1093/nar/1.suppl_1.s109

Cited by 13 publications

(3 citation statements)

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“…HPLC-UV-MS/MS analysis of the solution demonstrated that there was a single peak in the UV chromatogram at 240 nm and the mass spectrum of the peak exhibited a predominant peak at m/z 247.0, corresponding to the protonated molecular ion of 5,6-dihydro-5-azacytidine. 40 No other mass peak with appreciable intensity was detected and the conversion was considered quantitative with minimal degradation. Therefore, the reaction mixture was diluted to 100 mg/mL using water and stored at À808C as the stock solution of the IS.…”

Section: Experimental Materialsmentioning

confidence: 99%

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5‐aza‐2′‐deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method

Liu

Marcucci

Byrd

et al. 2006

Rapid Comm Mass Spectrometry

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Aberrant DNA methylation patterns resulting in gene transcriptional repression are observed in numerous cancers. Decitabine, a DNA methyltransferase inhibitor, is being clinically evaluated in patients with hematologic malignancies and solid tumors. Decitabine is rather unstable and decomposes to 1-beta-D-2'-deoxyribofuranosyl-3-guanylurea under basic conditions and several additional unknown products under neutral conditions. This has greatly limited application of pharmacokinetic assays to clinical development of decitabine. In this paper, a high-performance liquid chromatography/ultraviolet multi-stage mass spectrometry (HPLC-UV-MSn) study of the decomposition of decitabine in water and human plasma revealed that these previously unknown products are isomers of the intermediates formyl-1-beta-D-2'-deoxyribofuranosyl-3-guanylurea and 1-beta-D-2'-deoxyribofuranosyl-3-guanylurea. A HPLC tandem mass spectrometry (MS/MS) method for the determination of decitabine concentrations in human and rat plasma has been developed. This method was based on a specific fragmentation pathway of the molecular ion of decitabine at m/z 229 to generate a unique fragment ion at m/z 113 under collision-induced dissociation. Separation of decitabine and the stable internal standard dihydro-5-aza-cytidine from the endogenous interfering substance in plasma extract was carried out on a C18 Aquasil column under an isocratic elution with a mobile phase consisting of 5% water/acetonitrile and 10 mM ammonium formate. The detection of decitabine was via selected reaction monitoring (SRM, 229 > 113), and its ionization was enhanced by post-column addition of acetonitrile. Effects of sample preparation and handling parameters on the stability of decitabine were also evaluated in human plasma at various temperatures. The accuracy and precision of this assay showed a coefficient of variation of <15% over the range of 0.5-25 ng for rat plasma and 0.1-25 ng for human plasma injected on-column. Pharmacokinetics of decitabine in rats following intravenous doses of 1.0 and 5.0 mg/kg were characterized. In the rat, plasma concentration-time profiles were found to follow a biexponential decline and the pharmacokinetics was dose-independent. Application of this decitabine pharmacokinetic assay to human studies is therefore justified and ongoing.

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Section: Experimental Materialsmentioning

confidence: 99%

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5‐aza‐2′‐deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method

Liu

Marcucci

Byrd

et al. 2006

Rapid Comm Mass Spectrometry

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“…Decitabine is likely to have a dual mechanism of action: it may exert its effect via cytotoxic activity leading to cell death, but may also affect cell differentiation by demethylation leading to reactivation of genes that have previously been rendered inactive. Decitabine was first synthesized in appreciable amounts and formulated for therapeutic use in the early 1980s, and several methods were developed for its synthesis [20,35,36].…”

Section: Introductionmentioning

confidence: 99%

Decitabine: a historical review of the development of an epigenetic drug

Vos¹,

Overveld²

2005

Ann Hematol

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The development of decitabine from its synthesis in 1964 to the submission of a registration file has been described. Although the unique DNA-demethylating capacity of decitabine is known for a long time, its application is under continuing investigation. The use of decitabine in MDS, AML, CML, stem cell transplant, sickle cell anemia and thalassemia looks promising. The epigenetic dose seems lower than the cytotoxic dose. Whereas most drugs have matured after 40 years, decitabine is only at the beginning of a new development phase in epigenesis.

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“…The known 1-β-D-arabinufuranosyl-5-azacytosine 12 (ara-AC) is the major product 2-Deoxy-D-erythropentofuranosylaminocarbonylguanidinium Formate (7) This compound was prepared by hydrolysis of 2′-deoxy-5-azacytidine 15 with an aqueous solution of ammonia at a concentration of 1 mol l -1 , conducted as with 5-azacytidine 14 . This reaction was accompanied by partial anomerization, so that the product was a mixture of the α and β anomers.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the Polarographic Properties and Potential Carcinogenity of Some Hydroxyurea Derivatives by DC Polarography

Novotný

Vachálková

Pískala

1996

Collect. Czech. Chem. Commun.

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Polarographic reduction was studied for a series of 7 urea derivatives and the results were used to assess their potential carcinogenity. The polarographic reduction was examined in absolutely anhydrous dimethylformamide by DC polarography. In the conditions applied, the majority of the compounds was reduced within a single two-electron step, only biuret and its formyl derivative were reduced in two one-electron steps. The potential carcinogenity of the substances was assessed based on the tg α value of the slope of dependence of the polarographic wave height on the concentration of α-lipoic acid added as a test substance. For hydroxyurea, which is the only substance in this series for which a carcinogenic activity has been demonstrated, the tg α parameter attained a value of 0.290. Still higher values were obtained for the formyl derivatives -formylbiuret (0.362) and 2-carbamoyl-1-formylguanidine (0.510). So high tg α values warn of a significant potential carcinogenity. The other substances studied exhibited considerably lower tg α values, indicating that their potential carcinogenity will be low.

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Direct synthesis of 5-azapyrimidine 2′-deoxyribonucleosides. Hydrolysis of 5-aza-2′-deoxycytidine

Cited by 13 publications

References 0 publications

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5‐aza‐2′‐deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5‐aza‐2′‐deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method

Decitabine: a historical review of the development of an epigenetic drug

Investigation of the Polarographic Properties and Potential Carcinogenity of Some Hydroxyurea Derivatives by DC Polarography

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