3H-8-hydroxy-3-(β-D-2′-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one | 91021-93-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 3H-8-hydroxy-3-(β-D-2′-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one
• 英文别名: 3-(2-deoxy-β-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine；3H-8-hydroxy-3-(β-D-2'-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purin-9-one；3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-(3H)-one；1,N2-hydroxypropanodeoxyguanosine；hydroxy-1,N²-propanodeoxyguanosine；γ-OHPdG；3-(2-Deoxy-beta-D-erythro-pentofuranosyl)-4,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purin-10(3H)-one (~90%)；8-hydroxy-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10-one
• CAS: 91021-93-1
• 化学式: C₁₃H₁₇N₅O₅
• 分子量: 323.308
• InChiKey: INAGNQRTDPXONR-QRDCSKFFSA-N

物化性质

• 熔点：
  >190°C (dec.)
• 沸点：
  745.2±70.0 °C(Predicted)
• 密度：
  2.03±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  132
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3H-8-hydroxy-3-(β-D-2′-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one 在 sodium tetrahydroborate 作用下， 以 甲醇 、 水 、 二甲基亚砜 为溶剂， 反应 128.0h， 生成 1,3-bis(2'-deoxyguanosin-N2-yl)propane
  参考文献：
  名称：

  Interchain Cross-Linking of DNA Mediated by the Principal Adduct of Acrolein

  摘要：

  A DNA duplex containing the primary acrolein adduct, 3-(2-deoxy-beta -D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purin-10(3H)-one (2), of deoxyguanosine in a 5'-CpG sequence context spontaneously but reversibly formed an interchain cross-link with the exocyclic amino group of deoxyguanosine in the opposing chain. The linkage was sufficiently stable that the cross-linked duplex could be isolated by HPLC and characterized by MALDI-TOF mass spectrometry. Enzymatic degradation gave his-nucleoside 6, which was independently prepared by direct reaction of 2 with dGuo.

  DOI：

  10.1021/tx010127h
• 作为产物：
  描述：

  (2R,3S,5R)-5-[2-氟-6-(2-三甲基硅烷基乙氧基)嘌呤-9-基]-2-(羟基甲基)四氢呋喃-3-醇 在 sodium periodate 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 phosphate buffer 、 二甲基亚砜 为溶剂， 反应 7.0h， 生成 3H-8-hydroxy-3-(β-D-2′-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one
  参考文献：
  名称：

  含有丙烯醛和氯乙烯加合物的核苷和寡核苷酸的合成。

  摘要：

  氯乙烯和丙烯醛是重要的工业化学品。两者通过直接反应酶促氧化为氯环氧乙烷和丙烯醛后均形成DNA加合物，氯乙烯。鸟嘌呤N（2）位置的反应是主要途径。所得的2-氧代乙基和3-氧代丙基加合物分别自发环化为羟基乙醇和羟基丙烷衍生物。在暴露于这些诱变剂的DNA中已检测到两个环状加合物。已经开发了一种新方法，用于合成氯氧杂环丁烷和丙烯醛的脱氧鸟苷加合物，以及含有这些加合物的寡核苷酸。O（6）-[（（三甲基甲硅烷基）乙基] -2-氟-2'-脱氧肌苷与适当的氨基二醇反应，然后将二醇与NaIO（4）氧化裂解，可得到高收率的加合物。含有卤代核苷的寡核苷酸与氨基二醇的反应，然后是NaIO（4），可在寡核苷酸中有效地产生核苷。使用6-氯嘌呤9-（2'-脱氧核糖苷）类似地产生脱氧腺苷加合物。

  DOI：

  10.1021/tx990167+

文献信息

• Regioselective Formation of Acrolein-Derived Cyclic 1,<i>N</i>²-Propanodeoxyguanosine Adducts Mediated by Amino Acids, Proteins, and Cell Lysates
  作者：Fung-Lung Chung、Mona Y Wu、Ahmed Basudan、Marcin Dyba、Raghu G. Nath

  DOI：10.1021/tx3002252

  日期：2012.9.17

  ubiquitous environmental pollutant. It is also formed as a product of lipid peroxidation. Following ring closure via the Michael addition, Acr modifies deoxyguanosine (dG) in DNA by forming cyclic 1,N2-propanodeoxyguanosine adducts (OHPdG). The reactions of Acr with dG yield, depending on the direction of ring closure, two regioisomers, α- and γ-OHPdG, in approximately equal amounts. However, previous 32P-postlabeling

  丙烯醛 (Acr) 是香烟烟雾中的主要成分，是一种普遍存在的环境污染物。它也是脂质过氧化的产物。通过迈克尔加成环闭合后，Acr 通过形成环状 1, N 2 -丙脱氧鸟苷加合物 (OHPdG) 来修饰 DNA 中的脱氧鸟苷 (dG )。Acr 与 dG 的反应产生两种区域异构体，α-和 γ-OHPdG，数量大致相等，这取决于闭环的方向。然而，之前的32 P 标记后研究表明，γ 异构体主要在啮齿动物和人体组织的 DNA 中检测到。由于异构 OHPdG 加合物的潜在差异生物活性，确认和研究 γ 异构体区域选择性形成的化学基础很重要体内。在这项研究中，证实了 γ-OHPdG 加合物确实是体内形成的主要异构体，正如专门为 Acr 衍生的 dG 加合物开发的 LC-MS/MS 方法所证明的那样。此外，我们已经表明，在含氨基化合物（包括氨基酸、蛋白质和细胞裂解物）的存在下，γ-异构体的形成会增加。鉴定出似乎介导
• An Ammonium Bicarbonate-Enhanced Stable Isotope Dilution UHPLC-MS/MS Method for Sensitive and Accurate Quantification of Acrolein–DNA Adducts in Human Leukocytes
  作者：Ruichuan Yin、Shengquan Liu、Chao Zhao、Meiling Lu、Moon-shong Tang、Hailin Wang

  DOI：10.1021/ac3034695

  日期：2013.3.19

  Acrolein (Acr), a ubiquitous environmental pollutant, can react directly with genomic DNA to form mutagenic adducts without undergoing metabolic activation. To sensitively and accurately quantify Acr–DNA adducts (including structural isomers and stereoisomers) in human leukocytes, we developed an enhanced stable isotope dilution ultrahigh performance liquid chromatography (UHPLC)–tandem mass spectrometry (MS/MS) method using ammonium bicarbonate (NH4HCO3), which is thermally unstable and degrades readily to carbon dioxide and ammonia in heated gas phase. Interestingly, ammonium bicarbonate (as an additive to the mobile phase) not only improves the protonation of AcrdG adducts but also suppresses the formation of MS signal-deteriorating metal–AcrdG complexes during electrospray ionization, leading to the enhancement of their MS detection by 2.3–8.7 times. In contrast, routinely used ammonium salts (ammonium acetate and ammonium formate) and formic acid do not show similar enhancement. The developed method is potentially useful for enhancing ESI-MS detection of other modified 2′-deoxyribonucleosides that have difficulty in protonation and may form excess metal complexes during electrospray ionization. The limits of detection (LODs, S/N = 3) are estimated to be about 40–80 amol. By the use of the developed method, we found that the Acr adducts of three nucleotides (dG, dA, and dC) can be detected in human leukocytes. In addition to the known γ-AcrdG, α-AcrdA is also identified as an Acr-adduct of high abundance (2.5–20 adducts per108 nts).

  丙烯醛（Acrolein，Acr）是一种无处不在的环境污染物，可直接与基因组 DNA 发生反应，形成致突变加合物，而无需经过代谢活化。碳酸氢铵（NH4HCO3）热不稳定，在加热气相中很容易降解为二氧化碳和氨，为了灵敏、准确地定量检测人体白细胞中的 Acr-DNA 加合物（包括结构异构体和立体异构体），我们开发了一种增强型稳定同位素稀释超高效液相色谱（UHPLC）-串联质谱（MS/MS）方法。有趣的是，碳酸氢铵（作为流动相的添加剂）不仅能改善 AcrdG 加合物的质子化，还能抑制电喷雾离子化过程中形成会降低 MS 信号的金属-AcrdG 复合物，从而使其 MS 检测能力提高 2.3-8.7 倍。相比之下，常规使用的铵盐（醋酸铵和甲酸铵）和甲酸则没有类似的增强效果。所开发的方法可用于提高其他修饰的 2′-脱氧核苷酸的 ESI-MS 检测能力，因为这些核苷酸难以质子化，在电喷雾离子化过程中可能会形成过量的金属复合物。检测限（LODs，S/N = 3）估计约为 40-80 amol。通过使用所开发的方法，我们发现可以在人类白细胞中检测到三种核苷酸（dG、dA 和 dC）的 Acr 加合物。除了已知的γ-AcrdG外，α-AcrdA也被鉴定为高丰度的Acr加合物（每108 nts有2.5-20个加合物）。
• Development of a Method for Quantification of Acrolein−Deoxyguanosine Adducts in DNA Using Isotope Dilution-Capillary LC/MS/MS and Its Application to Human Brain Tissue
  作者：Xinli Liu、Mark A. Lovell、Bert C. Lynn

  DOI：10.1021/ac050624t

  日期：2005.9.1

  Acrolein is a highly reactive α,β-unsaturated aldehyde and is known to react with DNA forming exocyclic acrolein−deoxyguanosine adducts (Acro−dG). These aldehyde−DNA lesions may play a role in mutagenesis, carcinogenesis, and neurodegenerative diseases. In the present work, we described the development and evaluation of a highly sensitive and selective capillary liquid chromatography nanoelectrospray isotope dilution tandem mass spectrometry method for quantitatively analyzing Acro−dG in DNA hydrolysates. This was achieved by applying a stable isotope-labeled analogue Acro−dG-13C10,15N5 as an internal standard to the DNA to be analyzed and then hydrolyzing the DNA enzymatically to nucleosides. The acrolein-modified nucleosides were separated from normal nucleosides by capillary liquid chromatography and quantified by a high-capacity ion trap mass spectrometer in the MS/MS mode. The developed method achieved attomole-level sensitivity (limit of detection was 10 fg, 31 amol on column) for detection of pure Acro−dG adduct standards. The limit of quantification of Acro−dG adducts obtained in 10 μg of DNA hydrolysates was 1.5 fmol, which corresponded to 50 adducts/109 normal nucleosides. Application of this method to the analysis of Acro−dG adducts in acrolein (10-fold)-treated calf thymus DNA showed ∼830 lesion/106 DNA nucleosides using as low as 50 ng of DNA. Application of this method to DNA samples (1−2 μg) isolated from brain tissues from Alzheimer's disease subjects and age-matched controls demonstrated 2800−5100 Acro−dG adducts/109 DNA nucleosides. Statistically significant differences (P < 0.05) in levels of Acro−dG between AD subjects and controls were observed in DNA isolated from the hippocampus/parahippocampal gyrus.

  丙烯醛是一种高反应性 α,β-不饱和醛，已知会与 DNA 反应形成环外丙烯醛-脱氧鸟苷加合物 (Acro-dG)。这些醛-DNA 损伤可能在诱变、致癌和神经退行性疾病中发挥作用。在目前的工作中，我们描述了用于定量分析 DNA 水解产物中 Acro−dG 的高灵敏度和选择性毛细管液相色谱纳电喷雾同位素稀释串联质谱方法的开发和评估。这是通过将稳定同位素标记的类似物 Acro−dG-13C10,15N5 作为内标应用于待分析的 DNA，然后将 DNA 酶促水解为核苷来实现的。通过毛细管液相色谱将丙烯醛修饰的核苷与正常核苷分离，并通过高容量离子阱质谱仪在 MS/MS 模式下进行定量。所开发的方法实现了阿托摩尔水平的灵敏度（检测限为 10 fg，柱上 31 amol），用于检测纯 Acro−dG 加合物标准品。 10 μg DNA 水解产物中获得的 Acro−dG 加合物的定量限为 1.5 fmol，相当于 50 个加合物/109 个正常核苷。应用该方法分析丙烯醛（10 倍）处理的小牛胸腺 DNA 中的 Acro−dG 加合物，结果显示，使用低至 50 ng 的 DNA 即可发现约 830 个损伤/106 个 DNA 核苷。将该方法应用于从阿尔茨海默病受试者和年龄匹配对照的脑组织中分离的 DNA 样本（1−2 μg），结果显示有 2800−5100 个 Acro−dG 加合物/109 个 DNA 核苷。从海马/海马旁回分离的 DNA 中观察到 AD 受试者和对照组之间 Acro−dG 水平存在统计学显着差异 (P < 0.05)。
• The reaction of guanosine and 2′-deoxyguanosine with acrolein
  作者：G. Galliani、C. Pantarotto

  DOI：10.1016/s0040-4039(00)85935-3

  日期：1983.1
• Synthesis of Nucleosides and Oligonucleotides Containing Adducts of Acrolein and Vinyl Chloride
  作者：Lubomir V. Nechev、Constance M. Harris、Thomas M. Harris

  DOI：10.1021/tx990167+

  日期：2000.5.1

  oligonucleotides containing these adducts. Reaction of O(6)-[(trimethylsilyl)ethyl]-2-fluoro-2'-deoxyinosine with the appropriate aminodiol followed by oxidative cleavage of the diol with NaIO(4) gave the adducts in excellent yields. Reaction of oligonucleotides containing the halonucleoside with the aminodiols followed by NaIO(4) efficiently created the nucleosides in the oligonucleotides. Deoxyadenosine

  氯乙烯和丙烯醛是重要的工业化学品。两者通过直接反应酶促氧化为氯环氧乙烷和丙烯醛后均形成DNA加合物，氯乙烯。鸟嘌呤N（2）位置的反应是主要途径。所得的2-氧代乙基和3-氧代丙基加合物分别自发环化为羟基乙醇和羟基丙烷衍生物。在暴露于这些诱变剂的DNA中已检测到两个环状加合物。已经开发了一种新方法，用于合成氯氧杂环丁烷和丙烯醛的脱氧鸟苷加合物，以及含有这些加合物的寡核苷酸。O（6）-[（（三甲基甲硅烷基）乙基] -2-氟-2'-脱氧肌苷与适当的氨基二醇反应，然后将二醇与NaIO（4）氧化裂解，可得到高收率的加合物。含有卤代核苷的寡核苷酸与氨基二醇的反应，然后是NaIO（4），可在寡核苷酸中有效地产生核苷。使用6-氯嘌呤9-（2'-脱氧核糖苷）类似地产生脱氧腺苷加合物。