(1R,10R,11S)-11-羟基-4-甲基-8,13-二氧杂-2,6-二氮杂三环[8.2.1.02,7]十三-3,6-二烯-5-酮 | 15425-09-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: (1R,10R,11S)-11-羟基-4-甲基-8,13-二氧杂-2,6-二氮杂三环[8.2.1.02,7]十三-3,6-二烯-5-酮
• 英文名称: 2,5′-anhydrothymidine
• 英文别名: 2,5’-anhydrothymidine；3,5'-cyclo-2'-deoxyguanosine；2,5'-anhydro-thymidine；(6R)-8c-hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-6r,9c-epioxido-pyrimido[2,1-b][1,3]oxazocin-2-one；(6R)-8c-hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-6,9-epoxido-pyrimido[2,1-b][1,3]oxazocin-2-one；(6R)-8c-Hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-6,9-epoxido-pyrimido[2,1-b][1,3]oxazocin-2-on；O2,5/'-Anhydrothymidine；(1R,10R,11S)-11-hydroxy-4-methyl-8,13-dioxa-2,6-diazatricyclo[8.2.1.02,7]trideca-3,6-dien-5-one
• CAS: 15425-09-9
• 化学式: C₁₀H₁₂N₂O₄
• 分子量: 224.216
• InChiKey: QJUREIKZSJEEAH-XLPZGREQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1R,10R,11S)-11-羟基-4-甲基-8,13-二氧杂-2,6-二氮杂三环[8.2.1.02,7]十三-3,6-二烯-5-酮 在 乙二胺四乙酸 、 sodium phosphate 、 sodium chloride 作用下， 以 水 为溶剂， 反应 6.0h， 生成 胸腺嘧啶
  参考文献：
  名称：

  α,β-Methylene-2′-deoxynucleoside 5′-Triphosphates as Noncleavable Substrates for DNA Polymerases: Isolation, Characterization, and Stability Studies of Novel 2′-Deoxycyclonucleosides, 3,5′-Cyclo-dG, and 2,5′-Cyclo-dT

  摘要：

  We report synthesis and characterization of a complete set of alpha,beta-methylene-2'-dNTPs (alpha,beta-m-dNTP; N = A, C, T, G, 12-15) in which the alpha,beta-oxygen linkage of natural dNTP was replaced by a methylene group. These nucleotides were designed to be noncleavable substrates for DNA polymerases. Synthesis entails preparation of 2'-deoxynucleoside 5'-diphosphate precursors, followed by an enzymatic gamma-phosphorylation. All four synthesized alpha,beta-m-dNTPs were found to be potent inhibitors of polymerase beta, with K-i values ranging 1-5 mu M. During preparation of the dG and dT derivatives of alpha,beta-methylene diphosphate, we also isolated significant amounts of 3,5'-cyclo-dG (16) and 2,5'-cyclo-dT (17), respectively. These novel 2'-deoxycyclonucleosides were formed via a base-catalyzed intramolecular cyclization (N3 -> C5' and O2 -> C5' respectively). In acidic solution, both 16 and 17 underwent glycolysis, followed by complete depurination. When exposed to alkaline conditions, 16 underwent an oxidative deamination to produce 3,5'-cyc1o-2'-deoxyxanthosine (19), whereas 17 was hydrolyzed exclusively to dT.

  DOI：

  10.1021/jm800692a
• 作为产物：
  描述：

  3'-O-acetylthymidine 在 吡啶 、 silver(I) acetate 、 乙腈 、 sodium iodide 作用下， 生成 (1R,10R,11S)-11-羟基-4-甲基-8,13-二氧杂-2,6-二氮杂三环[8.2.1.02,7]十三-3,6-二烯-5-酮
  参考文献：
  名称：

  脱氧核糖核苷和相关化合物。第五部分环胸苷和其他胸苷衍生物。胸苷中糖苷中心的构型

  摘要：

  DOI：

  10.1039/jr9550000816

文献信息

• Synthesis of novel C-2 substituted pyrimidine nucleoside analogs
  作者：Martin Dunkel、P. Dan Cook、Oscar L. Acevedo

  DOI：10.1002/jhet.5570300540

  日期：1993.10

  A series of 2-(2-oxoalkylidene)-4(1H)-pyrimidinone nucleoside analogs were synthesized by the addition of the lithium enolates of methylketones to 2,5′- and 2,2′-anhydrouridines and to 2,5′-anhydrothymidines. Alternatively, 2-thiouridine was alkylated with bromomethyl ketones to yield 2-(2-oxoalkyl)thio-4(1H)-pyrimidinone ribofuranosides in good yields. These intermediates were subsequently transformed

  通过向2,5'-和2,2'-脱水尿苷中添加甲基酮的烯醇锂，合成了一系列2-（2-氧代亚烷基）-4（1 H）-嘧啶酮核苷类似物。 -脱水胸苷。或者，将2-硫代尿苷与溴甲基酮烷基化，以良好的产率得到2-（2-氧代烷基）硫基-4（1H）-嘧啶酮呋喃糖苷。这些中间体随后通过Eschenmoser硫磺挤出反应转化为标题化合物。2-（2-氧代亚烷基）-4-（1 H）-嘧啶酮核苷类似物在其1中显示烯醇质子信号H nmr光谱表明N-3与酮氧之间存在氢键。这些结构提供了具有沃森-克里克氢键潜力的官能团。
• Method for preparing radiolabeled thymidine
  申请人：Walsh C. Joseph

  公开号：US20050131224A1

  公开（公告）日：2005-06-16

  The invention is a novel method and precursor for preparing radiolabeled nucleosides. In particular, the invention is useful for preparing 3′-[ 18 F]fluorothymidine. The method uses an enol group that is attached to the 2-position on the pyrimidine ring. The enol group attenuates thymidines activity so that the thymidine is easily radiolabeled in short number of steps with good yield.

  这项发明是一种制备放射性标记核苷的新方法和前体。具体来说，这项发明对制备3'-[18F]氟胸苷很有用。该方法利用连接在嘧啶环的2位上的烯醇基团。这个烯醇基团减弱了胸苷的活性，使得胸苷可以在短时间内以良好的产率进行放射性标记。
• N-(Guanidinoethyl)-2′-deoxy-5-methylisocytidine exhibits selective recognition of a CG interrupting site for the formation of anti-parallel triplexes
  作者：Hidenori Okamura、Yosuke Taniguchi、Shigeki Sasaki

  DOI：10.1039/c3ob40472b

  日期：——

  novel nucleoside analogues for the formation of triplex DNA containing pyrimidine–purine inversion sites has been a challenging field. In this paper, we describe the design and synthesis of non-natural nucleoside analogues, N-substituted-2′-deoxy-5-methylisocytidine derivatives, and their evaluation for triplex formation. It has been shown that N-(guanidinoethyl)-2′-deoxy-5-methylisocytidine exhibits

  用于形成含嘧啶-嘌呤倒位位点的三链体DNA的新型核苷类似物的开发一直是一个充满挑战的领域。在本文中，我们描述了非天然核苷类似物N-取代的2'-脱氧-5-甲基异胞苷衍生物的设计与合成，以及它们对三链体形成的评估。已经显示出N-（胍基乙基）-2'-脱氧-5-甲基异胞苷显示出对CG中断位点的选择性识别并增强了反平行三链体的形成。
• Synthesis of Oligonucleotides Containing 2?-Deoxyisoguanosine and 2?-Deoxy-5-methylisocytidine Using Phosphoramidite Chemistry
  作者：Simona C. Jurczyk、Janos T. Kodra、J. David Rozzell、Steven A. Benner、Thomas R. Battersby

  DOI：10.1002/hlca.19980810502

  日期：——

  The synthesis of oligonucleotides containing 2′-deoxy-5-methylisocytidine and 2′-deoxyisoguanosine using phosphoramidite chemistry in solid-phase oligonucleotide synthesis is described. Supporting previous observations, the N,N-diisobutylformamidine moiety was found to be a far superior protecting group than N-benzoyl for 2′-deoxy-5-methylisocytidine. 2′-Deoxy-N2-[(diisobutylamino)methylidene]-5′-(4

  描述了在固相寡核苷酸合成中使用亚磷酰胺化学合成包含2'-脱氧-5-甲基异胞苷和2'-脱氧异鸟苷的寡核苷酸。支持先前的观察，发现N，N-二异丁基甲am部分是对于2'-脱氧-5-甲基异胞嘧啶而言比N-苯甲酰基更好的保护基。2′-脱氧-N 2 -[（（二异丁基氨基）亚甲基] -5′-（（4,4′-二甲氧基叔丁基）-5-甲基异胞苷3′-（2-氰基乙基二异丙基磷酰胺基）（1c）根据二甲氧基三苯甲基的释放，在标准的自动合成方案中掺入了多个连续的残基，偶联效率> 99％使用2'-脱氧-N 6 -[（（二异丁基氨基）亚甲基] -5'- O-（二甲氧基三苯甲基）-O 2-（二苯基氨基甲酰基）异鸟苷，3'-（2-氰基乙基）将标准方案的偶联时间延长至≥600s根据二甲氧基三苯甲基的释放，二异丙基亚磷酰胺（7e）成功结合了多个连续的2'-脱氧异鸟苷碱，偶联效率> 97％。
• [EN] PROTON ACTIVATED ATOMIC MEDICINE<br/>[FR] MÉDECINE ATOMIQUE ACTIVÉE PAR PROTONS
  申请人：UNIV VIRGINIA PATENT FOUNDATION

  公开号：WO2018237241A1

  公开（公告）日：2018-12-27

  The present application provides compositions and methods for preparing and using "heavy" nucleotide derivatives of thymidine or uridine by replacing the oxygen atom attached to one or more of positions with non-radioactive oxygen-18 (18O), administering it to a subject to target a tumor including incorporation into tumor cell DNA, and then treating the tumor with proton beam therapy to transmutate the 18O to 18F, resulting in a break of the new fluorine-phosphorous bond. This chemical event destabilizes ribose-phosphate DNA back-bone and base pairing thus produce single- and double strand breaks, clusters lesions that can lead to irreparable DNA damage and enhanced tumor cell killing. The atomic, chemical, and physical aspects result in the use of lower radiation doses and significantly alter acute and late morbidity of radiotherapy. Heavy thymidine and heavy uridine derivatives labeled with 18O have been made and tested.

  本申请提供了制备和使用“重型”胸腺嘧啶或尿嘧啶核苷酸衍生物的组合物和方法，通过用非放射性氧-18（18O）替换连接在一个或多个位置上的氧原子，将其注入到患者体内以靶向肿瘤，包括将其并入到肿瘤细胞DNA中，然后使用质子束治疗来转变18O为18F，从而破坏新的氟-磷键。这种化学事件不稳定了核糖-磷酸DNA骨架和碱基配对，从而产生单链和双链断裂、簇状损伤，可能导致不可修复的DNA损伤和增强的肿瘤细胞杀伤。原子、化学和物理方面的特性导致使用较低的辐射剂量，并显著改变了放射治疗的急性和迟发性发病率。已经制备和测试了标记有18O的重型胸腺嘧啶和重型尿嘧啶衍生物。