β-D-2'-deoxyribofuranosyl-3-guanylurea | 69304-65-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: β-D-2'-deoxyribofuranosyl-3-guanylurea
• 英文别名: 2'-deoxyriboguanylurea；Decitabine Deformyl Impurity；1-(diaminomethylidene)-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]urea
• CAS: 69304-65-0
• 化学式: C₇H₁₄N₄O₄
• 分子量: 218.213
• InChiKey: VGUQMXPKKFTIJO-VPENINKCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  143
• 氢给体数：
  5
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  地西他滨开环杂质 生成 β-D-2'-deoxyribofuranosyl-3-guanylurea
  参考文献：
  名称：

  高效液相色谱法分析5-氮杂-2'-脱氧胞苷的化学稳定性。

  摘要：

  通过高效液相色谱法分析了5-氮杂-2'-脱氧胞苷（I）在酸性，中性和碱性溶液中的化学稳定性。在碱性溶液中，我经历了可逆的快速分解为N-（甲酰米基）-N'-β-D-2-脱氧核糖呋喃糖基脲（II），后者不可逆地分解成1-β-D-2'-脱氧核糖呋喃糖基-3-胍基脲（ III）。确定该反应的拟一级反应速率常数。I在碱性溶液中的分解与先前报道的相关类似物5-氮杂胞苷的分解相同。但是，在中性溶液（或水中）中，I和5-氮杂胞苷的分解存在明显差异。在碱性溶液中，5-氮杂胞苷在中性溶液中形成相同的分解产物。但是，在中性解决方案中，我分解为II和三种未知化合物，它们在254 nm处发色。当在低温下在中性溶液中存储时，化合物I最稳定。

  DOI：

  10.1002/jps.2600701112

文献信息

• 2′-Deoxyriboguanylurea, the primary breakdown product of 5-aza-2′-deoxyribocytidine, is a mutagen, an epimutagen, an inhibitor of DNA methyltransferases and an inducer of 5-azacytidine-type fragile sites
  作者：Katarzyna Lamparska、Jarrod Clark、Gail Babilonia、Victoria Bedell、Wesley Yip、Steven S. Smith

  DOI：10.1093/nar/gks706

  日期：2012.10

  5-Aza-2′-deoxycytidine (5azaC-dR) has been employed as an inhibitor of DNA methylation, a chemotherapeutic agent, a clastogen, a mutagen, an inducer of fragile sites and a carcinogen. However, its effects are difficult to quantify because it rapidly breaks down in aqueous solution to the stable compound 2′-deoxyriboguanylurea (GuaUre-dR). Here, we used a phosphoramidite that permits the introduction of GuaUre-dR at defined positions in synthetic oligodeoxynucleotides to demonstrate that it is a potent inhibitor of human DNA methyltransferase 1 (hDNMT1) and the bacterial DNA methyltransferase (M. Eco RII) and that it is a mutagen that can form productive base pairs with either Guanine or Cytosine. Pure GuaUre-dR was found to be an effective demethylating agent and was able to induce 5azaC-dR type fragile sites FRA1J and FRA9E in human cells. Moreover, we report that demethylation associated with C:G → G:C transversion and C:G → T:A transition mutations was observed in human cells exposed to pure GuaUre-dR. The data suggest that most of the effects attributed to 5azaC-dR are exhibited by its stable primary breakdown product.

  5-阿扎-2′-脱氧胞苷（5azaC-dR）被用作DNA甲基化的抑制剂、化疗药物、致裂剂、诱变剂、脆弱位点的诱导剂和致癌物。然而，由于其在水溶液中迅速分解为稳定的化合物2′-脱氧核糖鸟苷脲（GuaUre-dR），因此其效应难以量化。在这里，我们使用了一种磷酰胺，使得可以在合成寡脱氧核苷酸中特定位置引入GuaUre-dR，以证明其是人类DNA甲基转移酶1（hDNMT1）和细菌DNA甲基转移酶（M. Eco RII）的强效抑制剂，并且它是一种诱变剂，可以与鸟嘌呤或胞嘧啶形成有效的碱基对。纯GuaUre-dR被发现是一种有效的去甲基化剂，能够在人体细胞中诱导5azaC-dR类型的脆弱位点FRA1J和FRA9E。此外，我们报告在暴露于纯GuaUre-dR的人类细胞中观察到与C:G → G:C反转和C:G → T:A转移突变相关的去甲基化。数据表明，归因于5azaC-dR的大部分效应实际上是其稳定的主要分解产物所体现的。
• Azacytosine analogs and derivatives
  申请人：Phiasivongsa Pasit

  公开号：US20060205685A1

  公开（公告）日：2006-09-14

  Compounds and compositions of azacytosine analogs and derivatives are provided. In one aspect of the invention, analogs or derivatives of decitabine and azacitidine are provided with modification at the 4- and 6-position of the triazine ring, at the 1′-6′position of the ribose ring, or combinations thereof. Methods of synthesizing and manufacturing these analogs and derivatives are also provided. These compounds can be formulated into pharmaceutical compositions that can be used for treating any disease that is sensitive to the treatment with decitabine or azacitidine, such as hematological disorders and cancer.

  提供了氮杂胞嘧啶类似物和衍生物的化合物和组合物。在发明的一个方面，提供了三嗪环的4-和6-位置、核糖环的1′-6′位置或二者的修饰的地西他滨和阿扎胞苷的类似物或衍生物。还提供了合成和制造这些类似物和衍生物的方法。这些化合物可以配制成药物组合物，用于治疗对地西他滨或阿扎胞苷治疗敏感的任何疾病，如血液疾病和癌症。
• Synthesis of N4-Alkyl-5-azacytidines and Their Base-Pairing with Carbamoylguanidines - A Contribution to Explanation of the Mutagenicity of 2'-Deoxy-5-azacytidine
  作者：Alois Pískala、Naeem B. Hanna、Milena Masojídková、Miroslav Otmar、Pavel Fiedler、Karel Ubik

  DOI：10.1135/cccc20030711

  日期：——

  A series of N⁴-alkyl-5-azacytidines 3a-3h were prepared by treatment of the 4-methoxy analogue 4 with the respective amines. In the case of propyl-, butyl-, sec-butyl-, benzyl- or furfurylamine, aggregates of azacytidines 3a-3e with their hydrolytic products 5a-5e were isolated. Similar aggregates were obtained with 1-methyl-5-azacytosine (6) and 2-(methylcarbamoyl)guanidine (7). Compound 7 was prepared by the reaction of guanidine with methyl isocyanate; the reaction of 2 or 3 equivalents gave the di- or tricarbamoyl derivatives 11 and 12, respectively. Cyclization of 7 and 11 with DMF dimethyl acetal afforded azacytosines 6 and 13, respectively. Aggregates of guanosine with 5-azacytosine nucleosides 1, 2 and 15 or of 5-aza-5,6-dihydrocytosine nucleosides 16 and 17 with 5-azacytidine (1) and its 2'-deoxy congener 2 have been prepared by co-crystallization of the respective pairs of nucleosides. The anomers of (deoxyribosylcarbamoyl)guanidine 20a and 20b have been prepared by hydrolysis of the deoxy nucleoside 2. An aggregate of the picrate (8a) of (ribosylcarbamoyl)guanidine 8 with cytidine (9) has been obtained by co-crystallization of both components. Reaction of the methoxy nucleoside 4 with tert-butylamine gave, by contrast to the above mentioned amines, the α-anomer of O-methylribosylisobiuret 22, which was cyclized by DMF dimethyl acetal to the α-anomer of N⁴,N⁴-dimethyl-5-azacytidine 24. The connection of the base-pairing ability of carbamoylguanidines with the mutagenicity of 2'-deoxy-5-azacytidine (2) as well as the mechanism of inhibition of DNA methyltransferase by this nucleoside analogue is discussed. In contrast to the unsubstituted 5-azacytidine (1) or its N⁴-methyl derivatives, none of the N⁴-alkyl derivatives exhibited any antibacterial or antitumor activity at 100 μg/ml or 10 μmol/l concentrations, respectively.

  一系列的 N^4-烷基-5-氮杂胞苷 3a-3h 通过将 4-甲氧基类似物 4 与相应的胺处理而制备。对于丙基、丁基、sec-丁基、苄基或糠基胺，分别分离得到氮杂胞苷 3a-3e 与其水解产物 5a-5e 的聚集体。与 1-甲基-5-氮杂胞嘧啶 (6) 和 2-(甲基氨基)胍 (7) 也得到了类似的聚集体。化合物 7 由胍与甲基异氰酸酯反应制备；2或3当量的反应产生了二或三氨基甲酰衍生物 11 和 12。化合物 7 和 11 与 DMF 二甲缩醛的环化分别得到氮杂胞嘧啶 6 和 13。用吉安嘌呤与 5-氮杂胞嘧啶核苷 1、2 和 15 或 5-氮杂-5,6-二氢胞嘧啶核苷 16 和 17，或者 5-氮杂胞苷 (1) 及其 2'-去氧同分异构体 2 的聚集体，通过共结晶制备。(去氧核糖基氨基甲酰)胍嘧啶的异构体 20a 和 20b 通过去氧核苷酸 2 的水解制备。(核糖基氨基甲酰)胍嘧啶的偏硝酸盐 (8a) 与胞苷 (9) 的聚集体通过两组分的共结晶得到。与上述胺不同，甲氧基核苷 4 与叔丁胺反应，得到了 α-异构体的 O-甲基核糖异尿素 22，它通过 DMF 二甲缩醛环化为 α-异构体的 N^4,N^4-二甲基-5-氮杂胞苷 24。讨论了氨基甲酰胍的碱基配对能力与 2'-去氧-5-氮杂胞苷 (2) 的致突变性以及这种核苷类似物对 DNA 甲基转移酶的抑制机制的关系。与未取代的 5-氮杂胞苷 (1) 或其 N^4-甲基衍生物不同，100 μg/ml 或 10 μmol/l 浓度下，N^4-烷基衍生物均未表现出任何抗菌或抗肿瘤活性。