Chemical decomposition of 5-aza-2'-deoxycytidine (Decitabine): kinetic analyses and identification of products by NMR, HPLC, and mass spectrometry.
Chemical decomposition of 5-aza-2'-deoxycytidine (Decitabine): kinetic analyses and identification of products by NMR, HPLC, and mass spectrometry.
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DOI：
10.1021/tx900131u
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发表时间：
2009-06
影响因子：
4.1
通讯作者：
Sowers, Lawrence C.
中科院分区：
文献类型：
--
作者：
Rogstad, Daniel K.;Herring, Jason L.;Theruvathu, Jacob A.;Burdzy, Artur;Perry, Christopher C.;Neidigh, Jonathan W.;Sowers, Lawrence C.
核苷类似物 5-氮杂-2′-脱氧胞苷（地西他滨，DAC）是临床使用的几种抑制 DNA 甲基转移酶的药物之一，导致新复制的 DNA 中 5-甲基胞嘧啶减少，并随后转录激活因胞嘧啶甲基化而沉默的基因。除了甲基转移酶抑制作用外，DAC 还具有毒性和潜在的致突变性，并且可以诱导 DNA 修复反应。造成这些事件的机制尚不清楚。 DAC 在水溶液中化学不稳定，但之前的报道对其半衰期以及在生理温度和 pH 值下的相应分解产物几乎没有达成共识，这可能会混淆对其作用机制和在人体中长期使用的研究。在这里，我们采用了一系列分析方法来估计动力学速率并表征生理温度和 pH 条件下的 DAC 分解产物。我们的结果表明，DAC 分解成大量产物，这些产物是通过三嗪环的水解打开和去甲酰化以及糖环结构的异头化和可能的其他变化而形成的。我们还讨论了与所使用的每种分析方法相关的优点和问题。本文报告的结果将有助于正在进行的研究和临床试验，旨在了解 DAC 和相关类似物的作用机制、毒性和可能的致突变性。
The nucleoside analog 5-aza-2′-deoxycytidine (Decitabine, DAC) is one of several drugs in clinical use that inhibit DNA methyltransferases, leading to a decrease of 5-methylcytosine in newly replicated DNA and subsequent transcriptional activation of genes silenced by cytosine methylation. In addition to methyltransferase inhibition, DAC has demonstrated toxicity and potential mutagenicity, and can induce a DNA-repair response. The mechanisms accounting for these events are not well understood. DAC is chemically unstable in aqueous solutions, but there is little consensus between previous reports as to its half-life and corresponding products of decomposition at physiological temperature and pH, potentially confounding studies on its mechanism of action and long-term use in humans. Here we have employed a battery of analytical methods to estimate kinetic rates and to characterize DAC decomposition products under conditions of physiological temperature and pH. Our results indicate that DAC decomposes into a plethora of products, formed by hydrolytic opening and deformylation of the triazine ring, in addition to anomerization and possibly other changes in the sugar ring structure. We also discuss the advantages and problems associated with each analytical method used. The results reported here will facilitate ongoing studies and clinical trials aimed at understanding the mechanisms of action, toxicity, and possible mutagenicity of DAC and related analogs.
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影响因子：
3.8
作者：
CHAN, KK;GIANNINI, DD;SADEE, W
通讯作者：
SADEE, W
影响因子：
3.8
作者：
LIN, KT;MOMPARLER, RL;RIVARD, GE
通讯作者：
RIVARD, GE
DOI：
10.1080/07328319908045594
发表时间：
1999-01-01
期刊：
NUCLEOSIDES & NUCLEOTIDES
影响因子：
--
作者：
Liu, MC;Luo, MZ;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
3.8
作者：
NOTARI, RE;DEYOUNG, JL
通讯作者：
DEYOUNG, JL
影响因子：
2.2
作者：
Liu, ML;Mao, XA;Lindon, JC
通讯作者：
Lindon, JC