溴脲苷 | 59-14-3

• 物质功能分类: 生物化工 - 核苷类药物 - 脱氧核苷酸及其类似物
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: 溴脲苷
• 中文别名: 5-溴-2-脱氧尿苷(BRDU)；溴尿苷；溴脲嘧啶苷；5-溴尿嘧啶-2`-脱氧核苷,5-溴-2`-脱氧尿核苷；5-溴-2'-脱氧尿苷；5-BR-2'-脱氧尿苷；5-溴去氧脲苷；5-溴-2`-脱氧尿核苷；5-溴-2-脱氧尿苷；5-溴-2"-脱氧尿苷；5'-溴尿嘧啶核苷；5'-溴脱氧尿苷；5-溴脱氧尿苷；BRDU
• 英文名称: 5-bromo-2'-deoxyuridine
• 英文别名: BrdU；bromodeoxyuridine；5-bromo-2′-deoxyuridine；5-bromo-2’-deoxyuridine；5-Brom-2'-desoxy-uridin；5-bromo-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione；5-bromodeoxyuridine；5-Bromdeoxyuridin；broxuridine；BrdUrd；5-Bromo-2'-deoxy-uridin；5-Brom-2'-deoxyuridin；5-Br-2'-Udr；5-bromo-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione
• CAS: 59-14-3
• 化学式: C₉H₁₁BrN₂O₅
• mdl: MFCD00006529
• 分子量: 307.101
• InChiKey: WOVKYSAHUYNSMH-RRKCRQDMSA-N

物化性质

• 熔点：
  191-194 °C (dec.)(lit.)
• 比旋光度：
  31 º (c=1, 0.1N NaOH)
• 密度：
  1.8573 (rough estimate)
• 溶解度：
  NH4OH:0.1Mat20℃C，透明，无色
• LogP：
  -0.290
• 物理描述：
  5-bromo-2'-deoxyuridine is a white crystalline powder. (NTP, 1992)
• 颜色/状态：
  Crystals from absolute ethanol
• 蒸汽压力：
  1.7X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Solid BrdU is stable in the dark to heat and humidity for 3 months at temperatures below 60 °C. On exposure to sunlight there is discoloration to grayish-brown. Ultraviolet irritations of frozen aqueous solutions of BrdU results in liberation of bromide ion and formation of a debrominated dimer, while radiolysis of aqueous solutions in the presence of oxygen yields mainly bromide, isodialuric acid deoxyriboside, and smaller amounts of various oxygenated derivatives.

• 旋光度：
  (c = 1, 0.1 N NaOH) [a]20 D = +31 ± 1°
• 分解：
  When heated to decomposition it emits very toxic fumes of /hydrogen bromide and nitrogen oxides/.
• 解离常数：
  pKa = 7.27 (imide nitrogen) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.555
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

BrdU在注射到小鼠和大鼠体内后，会以相当快的速度降解，至少通过两条代谢途径；一是通过糖苷键的水解，产生溴尿嘧啶和2-脱氧核糖，这可能是进一步代谢的前体。另一个是脱溴反应，通过释放溴离子得到证明。分子剩余部分进一步的命运尚未被研究。

BrdU is degraded at a fairly rapid rate in mice and rats upon injection, in at least two metabolic pathways; one is hydrolysis at the glycosyl bond to yield bromouracil and 2-deoxyribose which is presumably then further metabolized. The other is debromination which is evidenced by liberation of bromide ion. The further fate of the remainder of the molecule has not been investigated

来源:Hazardous Substances Data Bank (HSDB)

代谢

5-溴脱氧尿嘧啶通过胸腺嘧啶激酶磷酸化生成5-溴脱氧尿嘧啶磷酸盐。

5-bromodeoxyuridine is phosphorylated by thymidine kinase to produce 5-bromodeoxyuridine-phosphate. (L626)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

5-溴脱氧尿嘧啶作用于DNA。它通过碱基替换诱导随机的DNA点突变。经过一定数量的复制周期后，碱基对将从A-T变为G-C，或从G-C变为A-T。作为胸腺嘧啶类似物，5-溴脱氧尿嘧啶通常与腺嘌呤配对。

5-bromodeoxyuridine acts on DNA. It induces a random DNA point mutation via base substitution. The base pair will change from an A-T to a G-C or from a G-C to an A-T after a number of replication cycles. As a thymine analog, 5-bromodeoxyuridine normally pairs with adenine.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

未列在IARC（国际癌症研究机构）名录中。可能导致遗传性基因损害。

Not listed by IARC. May cause heritable genetic damage.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

5-溴脱氧尿苷是一种诱变剂（能引起突变），是一种细胞毒素、致畸剂和一种弱致癌物。其主要的有害效应包括遗传突变、贫血、生殖障碍（胎儿死亡或畸形）、白内障和皮肤刺激。如果吸入，它可能引起呼吸道刺激；如果接触皮肤，可能导致皮肤刺激；如果接触眼睛，可能引起眼睛刺激。作为一种生殖毒素，根据OSHA实验室标准，BrDU将被视为“特别危险的物质”。

5-bromodeoxyuridine is a mutagen (causes mutations), a cytotoxin, a teratogen and a weak carcinogen. The primary harmful effects are genetic mutation, anemia, reproductive disorders (fetal death or abnormality), cataracts, and skin irritation. It can cause respiratory tract irritation if inhaled, skin irritation if it contacts the skin and eye irritation if it contacts the eyes. As a reproductive toxin BrDU would be considered a “particularly hazardous substance” under the OSHA lab standard.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服（L626）；吸入（L626）；皮肤给药（L626）

Oral (L626) ; inhalation (L626) ; dermal (L626)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

5-溴脱氧尿嘧啶可以导致运动过度、腹泻、体重减轻，如果大量反复摄入，可能会导致死亡。

5-bromodeoxyuridine can cause hypermotility, diarrhea, weight loss and possibly death if large amounts are repeatedly ingested.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

十二名患者接受了连续静脉输注（24小时）溴脱氧尿苷（BUdR）治疗，剂量为每平方米650或1000毫克/天，最多持续两周。药理学研究显示，在输注650和1000毫克/平方米/天时，动脉血浆中的稳态水平分别为6 X 10-7摩尔/升和1 X 10-6摩尔/升。通过比较两名患者输注前后的体外辐射存活曲线（CFUc的D0-pre/D0-post增强比率分别为1.8[650 mg/平方米/天]和2.5[1000 mg/平方米/天]）来评估BUdR在正常骨髓中的摄取。使用抗-BUdR单克隆抗体和免疫组化，三名患者的活检中展示了BUdR在正常皮肤和肿瘤细胞中的体内掺入情况，结果显示正常皮肤中的细胞掺入量明显少于肿瘤（正常皮肤少于10%，而肿瘤高达50%至70%）。

Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/sq m/d for up to two weeks. ... Pharmacology studies revealed a steady-state arterial plasma level of 6 X 10-7 mol/L and 1 X 10-6 mol/L during infusion of 650 and 1,000 mg/sq m/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/sq m/d) and 2.5 (with 1,000 mg/sq m/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

BrdU从胃肠道吸收后，通过肠道外给药，并且可能通过胎盘吸收（因为它具有致畸作用）。

BrdU is absorbed from the gastrointestinal tract following parenteral injection and is presumably absorbed transplacentally (because of its teratogenic effects).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

分布和药代动力学：将BrdU注入到啮齿类动物的动脉内会导致广泛的降解...。大部分未降解的部分会整合到各种组织的DNA中，特别是结肠、胃、骨髓和脾脏。在怀孕小鼠腹膜内注射的氘标记BrdU也在母体和胚胎的肝脏中找到。

Distribution and pharmacokinetics: Intra-arterial injection of BrdU into rodents results in extensive degradation... . Most of the portion which is not so degraded is incorporated into DNA of various tissues, particularly the colon, stomach, bone marrow, and spleen. The label of intraperitoneally injected deuterated BrdU in pregnant mice is also found in the liver of both mothers and embryos.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

BrdU片在大鼠皮下植入后，血清中的BrdU浓度被测定。在5小时内，血液中BrdU的峰值浓度达到10微克/毫升。使用琼脂包衣片后，血液中的BrdU浓度减少了一半，且未发现峰值浓度。

BrdU tablets were implanted subcutaneously in rats, and BrdU concentrations were determined in the serum. Within 5 hr peak concentrations of 10 ug BrdU/mL blood were reached. ... With the use of agar-coated tablets, BrdU concentrations in the blood were reduced by half, and no peak concentration was found. ...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险品标志：
  Xn
• 安全说明：
  S26,S36/37/39
• 危险类别码：
  R68,R36/37/38
• WGK Germany：
  2
• 海关编码：
  29349990
• 危险品运输编号：
  OTH
• RTECS号：
  YU7350000
• 危险标志：
  GHS08
• 危险性描述：
  H340,H361
• 危险性防范说明：
  P201,P281,P308 + P313

制备方法与用途

生物活性

Bromodeoxyuridine（BrdU，5-Bromo-2'-deoxyuridine，BUdR）是一种核苷类似物，能够与胸腺嘧啶竞争性地整合到DNA中，用于检测增生细胞。

体外研究

在RG2大鼠胶质瘤细胞中，Bromodeoxyuridine表现出对癌细胞系和癌症干细胞数量扩增的诱导作用，并且剂量依赖性地抑制了其增殖。在H9细胞和BJ纤维母细胞中，Bromodeoxyuridine引起了细胞周期分布的变化。由于BrdU能够稳定整合到DNA中，因此可用于评估细胞增殖及其他相关细胞过程。

体内研究

在大鼠胶质瘤RG2肿瘤模型中，通过腹腔注射（300 mg/kg）或口服给予（0.8 mg/ml），Bromodeoxyuridine显著减缓了肿瘤的形成。

化学性质

Bromodeoxyuridine是一种无臭、无味的白色结晶性粉末。它难溶于水和甲醇，几乎不溶于氯仿和苯，但易溶于氢氧化钠溶液。熔点为193-197℃（分解），比旋度+23°（C=1，水中）。

用途

Bromodeoxyuridine作为脑瘤和头颈部肿瘤的放射增敏剂，能够提高放疗的效果。与其他抗代谢剂联合使用也能增强治疗效果。

类别

有毒物质

毒性分级

低毒

急性毒性

• 大鼠口服LD50：8400毫克/公斤
• 小鼠口服LD50：9100毫克/公斤

可燃性危险特性

热分解会释放有毒的氮氧化物和溴化物烟雾

储运特性

应存放在通风、低温、干燥的地方

灭火剂

水、干粉、二氧化碳、泡沫或沙土

反应信息

• 作为反应物：
  描述：

  溴脲苷 在 platinum(IV) oxide 氧气 作用下， 以 水 为溶剂， 反应 8.0h， 以85%的产率得到1-(5-bromouracil-1-yl)-1,2-dideoxy-β-D-erythro-pentofuranuronic acid
  参考文献：
  名称：

  Synthesis of a Carboxamide Linked U^Br∗U^BrDimer–Duplex and Triplex Stabilities of the Corresponding Oligodeoxynucleotides

  摘要：

  A U-Br*U-Br dimer was synthesized by connecting the appropiate nucleoside monomers through a 5-atom carboxamide linkage. The dimer was incorporated in oligodeoxynucleotides and investigated for hybridization properties toward single and double stranded DNA.

  DOI：

  10.1080/15257779508010721
• 作为产物：
  描述：

  [(2R,3S,5R)-5-(5-bromo-2,4-dioxopyrimidin-1-yl)-3-(4-chlorobenzoyl)oxyoxolan-2-yl]methyl 4-chlorobenzoate 在 氨 作用下， 以 甲醇 为溶剂， 反应 16.0h， 生成 溴脲苷
  参考文献：
  名称：

  5-取代的2'-脱氧尿苷异头体的立体选择性合成

  摘要：

  研究了5-取代的2,4-双(三甲基甲硅烷氧基)嘧啶与3,5-双(Op-氯苯甲酰基)-2-脱氧-α-D-呋喃核糖基氯的取代反应。在对硝基苯酚的存在下，β端基异构体立体选择性地形成，而有机碱的加入导致α端基异构体的立体选择性形成。反应的立体选择性取决于二甲硅烷基嘧啶的 5 位取代基、添加剂和每种试剂的浓度。5-取代的2'-脱氧-尿苷的α和β异头通过5-取代3',5'-二-O-(对-氯苯甲酰基)-2'-脱氧尿苷的α和β异头脱酰化合成。

  DOI：

  10.1246/bcsj.60.2073
• 作为试剂：
  描述：

  1-戊硫醇 、 12-Chloro-8,9,10,11-tetrahydro-7H-benzo[4,5]imidazo[1,2-a]cyclohepta[d]pyridine-6-carbonitrile 在 溴脲苷 作用下， 以 苯 为溶剂， 反应 4.0h， 以98%的产率得到12-Pentylsulfanyl-8,9,10,11-tetrahydro-7H-benzo[4,5]imidazo[1,2-a]cyclohepta[d]pyridine-6-carbonitrile
  参考文献：
  名称：

  Russell, Ronald K.; Nievelt, Caroline E. van, Journal of Heterocyclic Chemistry, 1995, vol. 32, # 1, p. 299 - 306

  摘要：

  DOI：

文献信息

• [EN] PYRROLOPYRIMIDINES<br/>[FR] PYRROLOPYRIMIDINES
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2009016132A1

  公开（公告）日：2009-02-05

  The present invention relates to compounds or pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to compounds that are polo-like kinase (PLKs) inhibitors useful for the treatment of disease states mediated by PLK, especially PLK4, in particular such compounds that are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumour growth, rheumatoid arthritis, restenosis and atherosclerosis.

  本发明涉及化合物或其药用盐，制备它们的方法，含有它们的药物组合物以及它们在治疗中的用途。该发明特别涉及一类极化样激酶（PLKs）抑制剂化合物，用于治疗由PLK介导的疾病状态，特别是PLK4，特别是在治疗涉及异常细胞增殖的病理过程中有用的化合物，如肿瘤生长、类风湿性关节炎、再狭窄和动脉粥样硬化。
• [EN] AZOLE COMPOUNDS AS PIM INHIBITORS<br/>[FR] COMPOSÉS D'AZOLE UTILISÉS EN TANT QU'INHIBITEURS DES PIM
  申请人：AMGEN INC

  公开号：WO2012129338A1

  公开（公告）日：2012-09-27

  The invention relates to bicyclic compounds of formulas I and Ia, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.

  该发明涉及公式I和Ia的双环化合物及其盐。在某些实施例中，该发明涉及Pim-1和/或Pim-2和/或Pim-3蛋白激酶活性或酶功能的抑制剂或调节剂。在更进一步的实施例中，该发明涉及包含本文所披露的化合物的药物组合物，以及它们在预防和治疗Pim激酶相关疾病和病症，尤其是癌症中的用途。
• ANTI-B7-H3 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
  申请人：AbbVie Inc.

  公开号：US20170355769A1

  公开（公告）日：2017-12-14

  The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.

  这项发明涉及B7同源物3蛋白（B7-H3）抗体和抗体药物结合物（ADCs），包括使用所述抗体和ADCs的组合物和方法。
• [EN] MACROCYLIC PYRIDINE DERIVATIVES<br/>[FR] DÉRIVÉS DE PYRIDINE MACROCYCLIQUES
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2015150557A1

  公开（公告）日：2015-10-08

  The present invention relates to substituted macrocylic pyrimidine derivatives of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention have EF2K inhibitory activity and optionally also Vps34 inhibitory activity. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

  本发明涉及式（I）的取代大环嘧啶衍生物，其中变量的含义如权利要求中所定义。根据本发明的化合物具有EF2K抑制活性，还可能具有Vps34抑制活性。本发明还涉及制备这种新化合物的方法，包含所述化合物作为活性成分的药物组合物，以及将所述化合物用作药物的用途。
• [EN] COMPOUNDS COMPRISING CLEAVABLE LINKER AND USES THEREOF<br/>[FR] COMPOSÉS COMPRENANT UN LIEUR CLIVABLE ET LEURS UTILISATIONS
  申请人：INTOCELL INC

  公开号：WO2019008441A1

  公开（公告）日：2019-01-10

  Provided are a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor.

  提供了一种包括可切割连接物的化合物，其用途，以及用于制备该化合物的中间体化合物，更具体地，本发明的包括可切割连接物的化合物可能包括具有特定功能或活性的活性剂（例如，药物，毒素，配体，用于检测的探针等），能够选择性释放活性剂的SO2官能团，以及通过外部刺激触发化学反应，物理化学反应和/或生物反应的官能团，并且还可以包括具有与所需靶受体结合特异性的配体（例如，寡肽，多肽，抗体等）。

表征谱图