N⁴-acetyl-1-<2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl>cytosine | 6742-08-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: N⁴-acetyl-1-<2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl>cytosine
• 英文别名: N⁴,2',3',5'-O-tetra-acetylarabinosylcytosine；β-D-arabinofuranosylcytosine tetracetate；4-N-acetyl-3',4',6'-O-triacetyl-cytarabine；4-acetylamino-1-(tri-O-acetyl-β-D-arabinofuranosyl)-1H-pyrimidin-2-one；O^2',O^3',O^5',N⁴-Tetraacetyl-1-β-D-arabinofuranosylcytosin；1-(2,3,5-Tri-O-acetyl-β-D-arabinofuranosyl)-N(4)-cytosin；Acetamide, N-(1,2-dihydro-2-oxo-1-(2,3,5-tri-O-acetylbeta-D-arabinofuranosyl)-4-pyrimidinyl)-；[(2R,3R,4S,5R)-5-(4-acetamido-2-oxopyrimidin-1-yl)-3,4-diacetyloxyoxolan-2-yl]methyl acetate
• CAS: 6742-08-1
• 化学式: C₁₇H₂₁N₃O₉
• 分子量: 411.368
• InChiKey: SABGQSSAGOWXJK-DMRZNYOFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  150
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N⁴-acetyl-1-<2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl>cytosine 在 碘 、 silver trifluoroacetate 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以34%的产率得到N4,2',3',5'-O-tetra-acetyl-5-iodoarabinosylcytosine
  参考文献：
  名称：

  有机氟化合物的研究。第35部分。用三氟甲基-铜络合物对嘧啶和嘌呤核苷进行三氟甲基化

  摘要：

  使用三氟甲基-铜络合物的溶液将卤代的核苷衍生物进行三氟甲基化，该溶液是通过将三氟甲基碘和铜粉在六甲基磷酸三酰胺中振摇并滤出过量的铜粉而制得的。以中等至良好的产率获得以下三氟甲基化的核苷：5-三氟甲基-尿苷，-脱氧尿苷，-胞苷，-脱氧胞苷和-阿拉伯糖基胞嘧啶；8-三氟甲基-腺苷，-脱氧腺苷和-肌苷；和6-三氟甲基核呋喃呋喃糖基嘌呤。该程序提供了许多三氟甲基化合物的简单合成方法。

  DOI：

  10.1039/p19800002755
• 作为产物：
  描述：

  乙酸酐 、 盐酸阿糖胞苷 在 吡啶 作用下， 反应 18.0h， 以129 g的产率得到N⁴-acetyl-1-<2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl>cytosine
  参考文献：
  名称：

  乙炔核苷。4.1-β-D-阿拉伯呋喃糖基-5-乙炔基胞嘧啶。改进了生物化学和抗病毒特性的合成和评估。

  摘要：

  由1-（2,3,5-三-O-乙酰基-β-D-阿拉伯呋喃糖基）胞嘧啶经碘化，然后与（三甲基甲硅烷基）乙炔偶合，制得5-乙炔基-1-β-D-阿拉伯呋喃糖基胞嘧啶（EAC）。解块。在50 microM时，发现EAC抑制1型和2型单纯疱疹病毒的体外复制超过99％。EAC还显示出对抗（E）-5-（2-溴乙烯基）-2'-脱氧尿苷的HSV-1菌株的活性，该菌株具有病毒诱导的胸苷激酶（TK）的改变。在100 microM时，EAC不会抑制白血病L1210和HeLa细胞的体外生长。EAC抵抗dCR-CR脱氨酶的作用，其脱氨率约为dCR的2％。该化合物是dCR激酶的弱底物，但被HSV-1-和HSV-2诱导的TK分别磷酸化了50％和30％。

  DOI：

  10.1021/jm00394a039

文献信息

• Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5′-hydroxyls for the syntheses of novel potential anticancer agents
  作者：Dennis M. Whitfield、Stephen P. Douglas、Ting-Hua Tang、Imre G. Csizmadia、Henrianna Y.S. Pang、Frederick L. Moolten、Jiri J. Krepinsky

  DOI：10.1139/v94-284

  日期：1994.11.1

  Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5′-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity.

  与预期相反，许多主要的羟基在糖基化反应中完全不活跃，或者以非常低的产率给出所需的糖苷，伴随着许多副反应产物。这些主要羟基的氢被显示为分子内氢键结合。由这些羟基对活化的糖基化试剂的亲核攻击形成的中间体可能会抵抗氢的提取。据推测，这种抵抗质子损失的现象是观察到的不活性的起源。研究表明，成功的糖基化反应发生在酸性条件下，这种条件下这种氢键不再存在。因此，首次利用三氯乙酰亚胺盐酸镓在氯仿中在三氟乙酸银的促进下，成功地对核苷的通常不活跃的5'-羟基进行了直接的半乳糖化。据指出，这种半乳糖化的抗癌核苷可能具有改善的生物特异性。
• DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles
  作者：Jhon Fernando Berrio Escobar、Diana Margarita Marquez Fernandez、Cristiano Giordani、Francesco Castelli、Maria Grazia Sarpietro

  DOI：10.1007/s10973-019-08780-x

  日期：2019.11

  Cytarabine (1-β-d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is used for the treatment of both acute and chronic myeloblastic leukemias and non-Hodgkin lymphoma. It has a very short plasma half-life and a very low oral bioavailability. To overcome these disadvantages, much effort has been focused on the design of cytarabine prodrugs. In this study, we have synthesized four different cytarabine prodrugs in order to increase the drug lipophilicity and the affinity of the prodrugs toward the biological membranes, as well as the lipophilic carriers. Differential scanning calorimetry was used to study the interaction of cytarabine and its prodrugs with multilamellar vesicles (MLVs) made of dimyristoylphosphatidylcholine (DMPC) and used as a model of biomembranes as well as a lipophilic carrier. The results showed that the 4-N-acetyl-2′,3′-5′-acetyl derivative and the prodrug with short chain fatty acids do not have a significant affinity with MLVs, whereas the prodrugs with long chain fatty acids have a stronger affinity with the MLVs with respect to cytarabine. The entity of the affinity depends on the fatty acids length. The increased affinity could be due to the fatty acid moieties which allow the molecule to insert among the phospholipid molecules. These results provide information on the interaction of these prodrugs with biomembranes and could be useful to design liposomes as carriers for the prodrugs.

  阿糖胞苷（1-β-d-arabinofuranosylcytosine，Ara-C）是一种嘧啶核苷类似物，用于治疗急慢性骨髓细胞白血病和非霍奇金淋巴瘤。它的血浆半衰期很短，口服生物利用度很低。为了克服这些缺点，人们一直在努力设计阿糖胞苷原药。在这项研究中，我们合成了四种不同的阿糖胞苷原药，以增加药物的亲脂性和原药对生物膜以及亲脂载体的亲和力。研究人员使用差示扫描量热法研究了阿糖胞苷及其原药与由二肉豆蔻酰磷脂酰胆碱（DMPC）制成的多胶束囊泡的相互作用，该囊泡被用作生物膜模型和亲油载体。结果表明，4-N-乙酰基-2′,3′-5′-乙酰基衍生物和短链脂肪酸原药与 MLVs 的亲和力并不明显，而相对于胞磷胆碱，长链脂肪酸原药与 MLVs 的亲和力更强。亲和力的大小取决于脂肪酸的长度。亲和力增强的原因可能是脂肪酸分子能使分子插入磷脂分子中。这些结果提供了这些原药与生物膜相互作用的信息，可能有助于设计脂质体作为原药的载体。
• BOBEK, MIROSLAV;KAVAI, I.;SHARMA, R. A.;GRILL, S.;DUTSCHMAN, G.;CHENG, Y.+, J. MED. CHEM., 30,(1987) N 11, 2154-2157
  作者：BOBEK, MIROSLAV、KAVAI, I.、SHARMA, R. A.、GRILL, S.、DUTSCHMAN, G.、CHENG, Y.+

  DOI：——

  日期：——
• Acetylenic nucleosides. 4. 1-(.beta.-D-Arabinofuranosyl)-5-ethynylcytosine. Improved synthesis and evaluation of biochemical and antiviral properties
  作者：Miroslav Bobek、I. Kavai、R. A. Sharma、S. Grill、G. Dutschman、Y. C. Cheng

  DOI：10.1021/jm00394a039

  日期：1987.11

  5-Ethynyl-1-beta-D-arabinofuranosylcytosine (EAC) was prepared from 1-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)cytosine by iodination followed by coupling with (trimethylsilyl)acetylene and deblocking. At 50 microM, EAC was found to inhibit the in vitro replication of herpes simplex virus type 1 and type 2 by greater than 99%. EAC also showed activity against a strain of HSV-1 resistant to (E)-

  由1-（2,3,5-三-O-乙酰基-β-D-阿拉伯呋喃糖基）胞嘧啶经碘化，然后与（三甲基甲硅烷基）乙炔偶合，制得5-乙炔基-1-β-D-阿拉伯呋喃糖基胞嘧啶（EAC）。解块。在50 microM时，发现EAC抑制1型和2型单纯疱疹病毒的体外复制超过99％。EAC还显示出对抗（E）-5-（2-溴乙烯基）-2'-脱氧尿苷的HSV-1菌株的活性，该菌株具有病毒诱导的胸苷激酶（TK）的改变。在100 microM时，EAC不会抑制白血病L1210和HeLa细胞的体外生长。EAC抵抗dCR-CR脱氨酶的作用，其脱氨率约为dCR的2％。该化合物是dCR激酶的弱底物，但被HSV-1-和HSV-2诱导的TK分别磷酸化了50％和30％。
• Studies on organic fluorine compounds. Part 35. Trifluoromethylation of pyrimidine- and purine-nucleosides with trifluoromethyl–copper complex
  作者：Yoshiro Kobayashi、Kenjiro Yamamoto、Toyohira Asai、Masanori Nakano、Itsumaro Kumadaki

  DOI：10.1039/p19800002755

  日期：——

  Halogenated nucleoside derivatives were trifluoromethylated using a solution of a trifluoromethyl–copper complex, which was prepared by shaking trifluoromethyl iodide and copper powder in hexamethylphosphoric triamide and filtering off the excess of copper powder. The following trifluoromethylated nucleosides were obtained in moderate to good yields: 5-trifluoromethyl-uridine, -deoxyuridine, -cytidine

  使用三氟甲基-铜络合物的溶液将卤代的核苷衍生物进行三氟甲基化，该溶液是通过将三氟甲基碘和铜粉在六甲基磷酸三酰胺中振摇并滤出过量的铜粉而制得的。以中等至良好的产率获得以下三氟甲基化的核苷：5-三氟甲基-尿苷，-脱氧尿苷，-胞苷，-脱氧胞苷和-阿拉伯糖基胞嘧啶；8-三氟甲基-腺苷，-脱氧腺苷和-肌苷；和6-三氟甲基核呋喃呋喃糖基嘌呤。该程序提供了许多三氟甲基化合物的简单合成方法。