6-氮杂尿苷 | 54-25-1

• 物质功能分类: 生物化工 - 核苷类药物 - 核苷中间体
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 6-氮杂尿苷
• 中文别名: 氮杂尿苷；氮尿苷
• 英文名称: 6-Azauridin
• 英文别名: 6-Azauridine；2-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione；2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazine-3,5-dione
• CAS: 54-25-1
• 化学式: C₈H₁₁N₃O₆
• mdl: MFCD00006472
• 分子量: 245.192
• InChiKey: WYXSYVWAUAUWLD-SHUUEZRQSA-N

物化性质

• 熔点：
  157-159 °C(lit.)
• 沸点：
  388.15°C (rough estimate)
• 密度：
  1.4866 (rough estimate)
• 溶解度：
  DMSO（轻微加热）、甲醇（轻微加热）、吡啶（轻微加热）、水
• 颜色/状态：
  Crystals from ether, ethanol
• 蒸汽压力：
  6.82X10-16 mm Hg at 25 °C (est)
• 旋光度：
  Max absorption (water): 262 nm (e= 6100); specific optical rotation: -132 deg at 24 °C/D (pyridine)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
• 解离常数：
  pKa = 6.63

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.625
• 拓扑面积：
  132
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

L1210细胞...与/6-氮尿嘧啶/ AzUrd一起孵化，含有一个新的254nm吸光度成分，在对照组细胞中未发现。它似乎是6-氮尿嘧啶-5'-三磷酸盐，因为它是色层谱中三磷酸盐区域唯一含有3H的峰，这是细胞与[3H]AzUrd孵化后的结果。

L1210 cells... incubated with /6-azauridine/ AzUrd contained a new 254 nm-absorbing component, not found in control cells. It appeared to be 6-azauridine-5'-triphosphate, since it was the only peak in the triphosphate region of the chromatogram which contained 3H after incubation of cells with [3H]AzUrd.

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿扎尿苷通过肠道微生物代谢成阿扎尿嘧啶。

... Azauridine is metabolized to azauracil by intestinal micoorganism ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿扎尿苷在细胞内转化为6-阿扎尿苷酸... /6-阿扎尿苷三乙酰衍生物/

Azauridine undergoes intracellular conversion to 6-azauridylic acid ... /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

代谢

口服给药后，大约45%的2',3',5'-三-O-乙酰-6-氮杂尿嘧啶（TA-6-氮杂尿嘧啶）以脱乙酰化产物的形式从大鼠尿液中排出，人体亦是如此。在大鼠尿液中，TA-6-氮杂尿嘧啶几乎完全以自由的6-氮杂尿嘧啶形式排出，而在人体中，还发现了大量的单-O-乙酰氮杂尿嘧啶（MA-6-氮杂尿嘧啶）。此外，在大鼠给药后48小时内收集的粪便中，约有35%的剂量以MA-6-氮杂尿嘧啶的形式存在。在大鼠的胆汁中没有发现TA-6-氮杂尿嘧啶或其脱乙酰化产物。在本研究中，无论是在大鼠的尿液、粪便还是胆汁中，都没有检测到6-氮杂尿嘧啶作为6-氮杂尿嘧啶的脱核苷酸化产物。

After oral administration about 45 per cent of 2',3',5'-tri-O-acetyl-6-azauridine (TA-6-azauridine) is eliminated in the urine of rats, as well as in man, in the form of its deacetylation products. In the urine of rats, TA-6-azauridine is excreted almost exclusively in the form of free 6-azauridine whereas in man a substantial amount of mono-O-acetyl-azauridine (MA-6-azauridine) also was found. Furthermore, about 35 per cent of the dose was found in the form of MA-6-azauridine in the feces of rats collected during 48 hr after the administration. Neither TA-6-azauridine nor its deacetylation products are excreted in the bile of rats. 6-Azauracil was not detected as a deribosylation product of 6-azauridine neither in the urine or feces nor in the bile of rats under study. /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在第一阶段研究中，对16名未经选择的不可切除肝细胞癌患者进行了D-半乳糖胺和6-氮尿嘧啶的261个周期治疗，然后再进行5-氟尿嘧啶治疗。30%的患者在没有肿瘤进展迹象且体能状态未改变的情况下存活了超过1年。这种化疗方法的兼容性相当令人满意。唯一的肝外副作用是白细胞减少和/或血小板减少，这在减少5-氟尿嘧啶剂量后是可逆的。到目前为止治疗的16名患者的异质性不允许对报告的临床观察和结果进行明确的统计分析。

Sixteen unselected patients with non-resectable hepatocellular carcinoma were treated in a phase I study with 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine. Thirty % of the patients survived for more than 1 yr without signs of tumor progression and with an unchanged performance status. The compatibility of this chemotherapeutical method was quite satisfactory. The only extrahepatic side effect was a leukcopenia and/or thrombocytopenia which was reversible upon reduction of the 5-fluorouridine dose. The heterogeneity of the 16 patients treated to date does not allow a definite statistical evaluation of the reported clinical observations and results.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

这项研究探讨了吡哆醇对6-氮尿嘧啶三乙酯（6-AzUrd-TA）诱导的高β-丙氨酸血症在新西兰白兔中的影响。在三个实验中，每组动物均通过灌胃给药：第1组（对照组），饮用水；第2组，6-AzUrd-TA；第3组，6-AzUrd-TA加吡哆醇。在对照组或6-AzUrd-Ta及6-AzUrd-TA加吡哆醇处理动物的预处理样本中未发现β-丙氨酸，但在连续4天和7天给予1.0 g/kg和0.5 g/kg体重剂量的6-AzUrd-TA处理后，发现了高浓度的这种氨基酸（191.0 ± 91.6，220.2 ± 116.3，103.2 ± 64.4 nmol/ml）。在三个实验中，同时给予每日50 mg/kg体重剂量的吡哆醇显著（p ≤ 0.05）降低了药物诱导的高β-丙氨酸血症。这些结果表明，每日重复口服6-AzUrd-Ta会导致血清β-丙氨酸升高，而口服吡哆醇可以部分预防这种情况。它们还间接支持了6-AzUrd-TA诱导的高β-丙氨酸血症至少部分是由抑制了使用磷酸吡哆醛作为辅酶的β-丙氨酸降解酶所致的假设。/6-氮尿嘧啶三乙酯/

The effect of pyridoxine on 6-azauridine triacetate (6-AzUrd-TA) induced hyper beta-alaninemia was studied in New Zealand albino rabbits in three experiments. In each of the three experiments the animals were admin by gavage: Group 1 (Control), drinking water; Group 2, 6-AzUrd-TA; and Group 3, 6-AzUrd-TA with pyridoxine. While no beta-alanine was found in the control group or in pretreatment samples of the 6-AzUrd-Ta and 6-AzUrd-TA plus pyridoxine treated animals, high concn of this amino acid (191.0 + or - 91.6, 220.2 + or - 116.3, 103.2 + or - 64.4 nmol/ml) were found on the fourth and seventh days of 6-AzUrd-TA treatment with daily doses of 1.0 g/kg and 0.5 g/kg body weight, respectively. The drug induced hyper beta-alaninemia was significantly (p < or = 0.05) reduced in all three experiments by simultaneous pyridoxine admin in daily doses of 50 mg/kg body weight. These results indicate that daily repeated oral admin of 6-AzUrd-Ta causes elevation of serum beta-alanine, which can be partially prevented by oral admin of pyridoxine. They also indirectly support the hypothesis that 6-AzUrd-TA induced hyper beta-alaninemia is at least partially caused by the inhibition of beta-alanine degrading enzymes, that use pyridoxal phosphate as a coenzyme. /6-Azauridine triacetate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

25种代谢物（包括嘌呤、嘧啶、核苷和核苷酸）与6-氮尿嘧啶（AzUrd）对新城疫病毒（NDV）复制的抑制作用进行了测试。除了脱氧腺苷和环磷酸腺苷外，所有天然腺嘌呤衍生物与AzUrd都表现出了与ATP相似的协同效应。谷氨酰胺与AzUrd联合使用并没有抑制NDV的复制。AzUrd与腺嘌呤衍生物联合使用的抑制作用可以通过鸟苷、尿苷和胞苷逆转，但黄嘌呤或黄嘌呤酸无法逆转。

Twenty-five metabolites (purines, pyrimidines, nucleosides and nucleosides) were tested for their simultaneous action with 6-azauridine (AzUrd) in inhibition of Newcastle disease virus (NDV) replication. With the exception of deoxyadenosine and cyclic AMP all natural adenine derivatives exerted a synergic effect with AzUrd like ATP. Glutamine in combination with AzUrd did not inhibit NDV replication. The inhibitory effect of the combination of AzUrd and adenine derivatives was reversible by guanosine, uridine and cytidine but not by orotic acid or orotidylic acid.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

药物长期使用后出现的中度贫血，特点是轻微的巨幼红细胞性改变、网织红细胞减少和血浆铁浓度升高... /6-阿唑尿嘧啶三乙酰衍生物/

/SIGNS AND SYMPTOMS/ Moderate anemia, characterized by mild megaloblastic changes, reticulocytopenia, and elevated plasma iron concn, occurs after chronic use of high doses of drug ... /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/SIGNS AND SYMPTOMS/ 表明造血抑制似乎相对选择性地影响红细胞生成，对正常白细胞或血小板计数几乎没有影响，如果有的话。 /6-Azauridine 三乙酰衍生物/

/SIGNS AND SYMPTOMS/ Hematopoietic suppression appears to be relatively selective for erythropoiesis, with very little if any effect noted on normal leukocyte or platelet counts. /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿扎瑞宾在口服给药后吸收良好...吸收后，阿扎瑞宾在血液中几乎完全脱乙酰化为阿扎/阿扎尿苷/，可检测到一些单乙酰衍生物。阿扎的血浆浓度峰值在2到4小时后达到，观察到血浆消失曲线的半衰期大约为6到8小时。/6-阿扎尿苷三乙酰衍生物/

Azaribine is well absorbed after oral admin ... After absorption, azaribine is almost entirely deacetylated to azur /azauridine/ in blood, with some monoacetyl deriv detectable. Peak plasma concn of azur are reached after 2 to 4 hr, and plasma disappearance curve with half-time of approx 6 to 8 hr is observed. /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

与阿唑尿嘧啶不同，阿唑/阿唑尿嘧啶/不会穿过血脑屏障，并且在脑脊液中无法检测到。当遇到神经毒性表现时，在脑脊液中可以测量到显著的阿唑尿嘧啶浓度... 大约95%的摄入剂量的阿唑嘧啶会在16小时内以阿唑的形式随尿液排出体外。/6-阿唑尿嘧啶三乙酰衍生物/

Unlike azauracil, azur /azauridine/ does not cross blood-brain barrier and is not detectable in CSF. When neurotoxic manifestations have been encountered, significant concn of azauracil ... measured in CSF. Approx 95% of ingested dose of azaribine is excreted in urine as azur within 16 hr. /6-Azauridine triacetyl deriv/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

2',3',5'-三乙酰-6-氮杂尿苷通过口服给药给十一位患有晚期肿瘤疾病的病人。这种化合物与游离的6-氮杂尿苷不同，能从消化道快速吸收。在服用乙酰化衍生物的剂量间隔的8小时内，血液中维持了显著的6-氮杂尿苷水平。通过对静脉注射的标记有碳-14的尿苷酸和尿中尿苷和尿苷酸的排泄情况进行研究，证明了在接受治疗的病人中，尿苷酸转化为尿苷核苷酸的过程受到了抑制。观察到的代谢效应和临床变化与静脉给药同等剂量的6-氮杂尿苷所产生的效果相当。/2',3',5'-三乙酰-6-氮杂尿苷/

2',3',5'-Triacetyl-6-azauridine was administered orally to eleven patients with far advanced neoplastic disease. The compound was absorbed rapidly from the gastrointestinal tract, in contrast to free 6-azauridine. Significant blood levels of 6-azauridine were maintained during the 8-hour period intervening between doses of the acetylated derivative. Depression of the conversion of orotic acid to uridine nucleotides was demonstrated in patients undergoing therapy, by studies of the fate of intravenously injected orotic acid-7-C14 and of the urinary excretion of orotidine and orotic acid. The metabolic effects and clinical changes observed were comparable to those produced by equivalent doses of intravenously administered 6-azauridine. /2',3',5'-Triacetyl-6-azauridine/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在正常大鼠和佐剂诱导的多发性关节炎大鼠中，给予(14)C-6-氮尿嘧啶后，(14)C的分布相似...除了后一组动物的肝脏(14)C浓度是前者的两倍。静脉注射后约1小时...给怀孕大鼠，胎儿中(14)C的浓度是母体循环中浓度的三分之一。

DISTRIBUTION OF (14)C WAS SIMILAR IN NORMAL RATS & RATS WITH ADJUVANT INDUCED POLYARTHRITIS, AFTER ADMIN OF (14)C-6-AZAURIDINE...EXCEPT THAT HEPATIC (14)C CONCN WERE TWOFOLD HIGHER IN LATTER GROUP OF ANIMALS. ABOUT 1 HR AFTER IV DOSE...TO PREGNANT RATS, FETAL CONCN OF (14)C WERE ONE-THIRD THOSE OF MATERNAL CIRCULATION.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S36
• 危险类别码：
  R20/21/22
• WGK Germany：
  3
• 海关编码：
  29349990
• RTECS号：
  XY8575000
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P280
• 危险品运输编号：
  2811
• 危险性描述：
  H302,H312,H332,H350

反应信息

• 作为反应物：
  描述：

  6-氮杂尿苷 在 吡啶 、 4-二甲氨基吡啶 、 氨 、 氯化铵 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 三氯氧磷 作用下， 以 吡啶 、 甲醇 、 乙腈 为溶剂， 反应 54.5h， 生成 6-氮杂胞苷
  参考文献：
  名称：

  Biochemical Detection of Cytidine Protonation within RNA

  摘要：

  Perturbation of active site functional group pK(a)s is an important strategy employed by protein enzymes to achieve catalysis. There is increasing evidence to indicate that RNAs also utilize functional group pK(a) perturbation for folding and reactivity. one of the best candidates for a functionally relevant pK(a) perturbation is the N3 of C (pK(a) 4.2), which could be sufficiently raised to allow protonation near physiological pH. Here we report the synthesis and use of a series of alpha -phosphorothioate tagged cytidine analogues whose altered N3 pK(a)s make it possible to efficiently detect functionally relevant protonation events by nucleotide analogue interference mapping. 6-Azacytidine (n(6)C alphaS) and 5-fluorocytidine (f(5)C alphaS) both have enhanced acidity at the N3 position (pK(a) 2.6 and 2.3, respectively) but leave the hydrogen bonding face of C otherwise unaffected. In contrast, pseudoisocytidine (Psi iC alphaS) is a charge neutral analogue that mimics the hydrogen bonding character of protonated C. To test the utility of these analogues, we characterized the C300(+)-G97-C277 mutant form of the Tetrahymena group I intron, which is predicted to require C300 protonation for ribozyme folding and reactivity. At neutral to alkaline pHs, C300 was the only site of n(6)C alphaS and f(5)C alphaS interference within the intron, yet both interferences were rescued at acidic pH. Furthermore,Psi iC alphaS substitution at C300 resulted in enhanced activity at alkaline pHs, consistent with the presence of an N3 proton under the pH conditions studied. Interference mapping with these analogues provides an efficient and sensitive means to identify every site within an RNA where cytidine protonation is important for RNA function and may make it possible to identify C's that participate in general acid/base catalysis within ribozyme active sites.

  DOI：

  10.1021/ja001918t
• 作为产物：
  描述：

  6-氮杂脲嘧啶 在 Escherichia coli 作用下， 生成 6-氮杂尿苷
  参考文献：
  名称：

  Skoda et al., Collection of Czechoslovak Chemical Communications, 1957, vol. 22, p. 1330 - 1332

  摘要：

  DOI：

文献信息

• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• CYCLIC ETHER PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20140088117A1

  公开（公告）日：2014-03-27

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I的环醚吡唑-4-基-杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2为环醚，X为噻唑基、吡啶基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物进行体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• [EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017197240A1

  公开（公告）日：2017-11-16

  Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

  本文提供了ASH1L活性的小分子抑制剂，促进ASH1L降解的小分子以及它们的使用方法，用于治疗疾病，包括急性白血病、实体肿瘤和其他依赖于ASH1L活性的疾病。

表征谱图