3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮 | 77439-76-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氢呋喃
• 中文名称: 3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮
• 中文别名: 3-氯-4(二氯甲基)5-羟基-2(5H)-呋喃酮
• 英文名称: 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone
• 英文别名: 3-chloro-4-(dichloromethyl)-5-hydroxy-2,5-dihydrofuran-2-one；4-chloro-3-(dichloromethyl)-2-hydroxy-2H-furan-5-one
• CAS: 77439-76-0
• 化学式: C₅H₃Cl₃O₃
• 分子量: 217.436
• InChiKey: WNTRMRXAGJOLCU-UHFFFAOYSA-N

物化性质

• 沸点：
  311.99°C (rough estimate)
• 密度：
  1.7771 (rough estimate)
• 溶解度：
  氯仿（微溶）、乙酸乙酯（微溶）
• 蒸汽压力：
  1.64X10-6 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

...在大鼠和雄性小鼠静脉注射MX（0.2毫克/千克）后，更大比例的MX衍生放射性物质（71-73%）通过尿液排出。大部分MX衍生放射性物质在给药后的前24小时内排出。MX转化为尿液和胆汁代谢物。一种主要的高度极性尿液代谢物被暂时鉴定为1-羟基-1,2,2-乙烷三羧酸。这种代谢物可能是由MX降解产物2-羟基-3-甲酰基-4-氧代-2-丁烯酸转化而来。

... A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid.

来源:Hazardous Substances Data Bank (HSDB)

代谢

MX在体内被广泛解毒，因此不太可能对系统性组织的遗传物质造成损害，除非在相对较高的剂量下，解毒途径变得饱和。

... MX is extensively detoxified in vivo and is unlikely to cause genetic damage in systemic tissues except at relatively high doses where detoxification pathways become saturated...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

MX在人体内的致癌性证据不足。在实验动物中，MX的致癌性证据有限。MX是一种强效的直接诱变剂，主要在大肠杆菌和哺乳动物细胞中诱导GC到TA的转突变。它在大肠杆菌和哺乳动物细胞中以及在活体啮齿动物中诱导DNA损伤。MX在哺乳动物细胞和大鼠中是染色体的诱变剂，并且能在体外诱导哺乳动物细胞转化。大鼠与MX相关的甲状腺肿瘤是由TSH介导的激素促进作用以外的机制引起的。总体评估：3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮(MX)可能对人类致癌（2B组）。

There is inadequate evidence in humans for the carcinogenicity of MX. There is limited evidence in experimental animals for the carcinogenicity of MX. MX is a potent, direct-acting mutagen that induces primarily GC to TA transversions in both bacterial and mammalian cells. It induces DNA damage in bacterial and mammalian cells as well as in rodents in vivo. MX is a chromosomal mutagen in mammalian cells and in rats, and it induces mammalian cell transformation in vitro. The MX-associated thyroid gland tumors in rats are caused by mechanisms other than TSH-mediated hormonal promotion. Overall evaluation 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is possibly carcinogenic to humans (Group 2B).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮

IARC Carcinogenic Agent:3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第84卷：（2004年）一些饮用水消毒剂和污染物，包括砷

IARC Monographs:Volume 84: (2004) Some Drinking-water Disinfectants and Contaminants, including Arsenic

来源:International Agency for Research on Cancer (IARC)

毒理性

• 相互作用

BALB/cABOM雄性小鼠（初始数量未指定），4周龄，每周一次腹腔注射7 mg/kg bw偶氮甲烷或0.9%氯化钠（载体对照）持续2周。一周后，动物通过直肠内给药0或20 mg/kg bw MX（94%纯度，溶于pH 3.4-4.0的无菌水中）每周三次，持续6周，总MX剂量为360 mg/kg，或者每周三次40 mg/kg bw MX持续4周，总MX剂量为480 mg/kg。所有小鼠在实验开始后15周处死，最后一次给药后6或8周。取出小肠、结肠和盲肠。对结肠和盲肠进行异常隐窝灶评分，对小肠、结肠和盲肠进行肿瘤评分……与氯化钠或偶氮甲烷相比，MX的两种剂量都没有增加每根结肠的异常隐窝灶发生率。每个处理组的大多数小鼠，包括载体对照组，都有小肿瘤（0.3-0.6毫米，每小肠1-16个）。一只接受偶氮甲烷和40 mg/kg bw MX的小鼠有一个结肠肿瘤……（国际癌症研究机构工作组指出偶氮甲烷的品系和剂量不足）。

Groups of male BALB/cABOM mice (initial numbers unspecified), 4 weeks of age, were administered an intraperitoneal injection of 7 mg/kg bw azoxymethane or 0.9% sodium chloride (vehicle control) once a week for 2 weeks. One week later, animals were administered 0 or 20 mg/kg bw MX (94% pure dissolved in sterile water at pH 3.4-4.0) intrarectally three times weekly for 6 weeks to give a total MX dose of 360 mg/kg or 40 mg/kg bw MX three times weekly over 4 weeks, giving a total MX dose of 480 mg/kg. All mice were killed 15 weeks after the start of the experiment, 6 or 8 weeks after the last dose. The small intestine, colon and cecum were removed. The colon and cecum were scored for altered crypt foci and small intestine, colon and cecum were scored for tumors ... . Neither dose of MX increased the incidence of aberrant crypt foci per colon when compared with sodium chloride or azoxymethane. ... Most mice in every treatment group, including the vehicle control, had small tumors (0.3-0.6 mm, 1-16 per small intestine). One mouse receiving azoxymethane and 40 mg/kg bw MX had a colon tumor ... . (The IARC Working Group noted the inadequacy of the strain and dose of azoxymethane.)

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

放射性物质在口服给予雄性和雌性小鼠以及雌性大鼠单剂量0.2至20 mg/kg的(14)C标记的MX后72小时内迅速被吸收并几乎等量地通过尿液(42-54%)和粪便(40-51%)排出。在雌性大鼠和雄性小鼠静脉注射(0.2 mg/kg)后，较大比例的MX相关放射性物质(71-73%)通过尿液排出。大部分MX相关放射性物质在给药后24小时内排出。口服给药后，组织的放射性物质与血液的比例最高，依次为：前胃(>100)、腺胃、肠道和肾脏。静脉给药导致血液中的放射性物质水平较高且持续时间较长，与口服给药相比。因此，MX的分布似乎主要受其化学反应性的影响，放射性物质最高浓度出现在给药部位。

... Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 hr following oral administration of (14)C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. ... Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮(MX)的药代动力学在一次口服或静脉给药后在大鼠体内进行了评估，使用的是14C标记的化合物。从尿液中排出的情况来看，20至35%的剂量从胃肠道吸收进入循环系统。血液中放射性活性的平均消除半衰期(T1/2 k10)为3.8小时。血液中的放射性活性残留持续了数天。胃肠道和泌尿道内衬的器官、肾脏、胃、小肠和膀胱含有最高的放射性活性。放射性活性在肾脏中下降得最慢。尿液是主要的排泄途径。在12小时内，尿液中有77%的总排泄量，在24小时内达到90%。空气中没有呼出放射性活性，这表明通过呼吸消除的过程并未发生。在静脉给药14C-MX后，T1/2 k10要长得多，为22.9小时，总消除半衰期(T1/2 beta)为42.1小时。结果表明，MX从胃肠道吸收到相当大的程度，并且非常迅速地通过尿液排出。MX或其代谢物的一部分在血液中保留的时间较长。MX的药代动力学并不表明在持续暴露后会大量积累MX在组织中。

The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C-MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half-life (T1/2 beta), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在另一项实验中，给维斯特大鼠注射了2毫克/千克（14C）MX的剂量，并在2小时和6小时后测定了组织中的放射性。2小时后，放射性最高的是肾脏，其次是胃、回肠、膀胱和肝脏。在6小时时，肾脏和膀胱中的放射性浓度显著降低，而在胃肠道的降低程度较小。

In another experiment, a dose of 2 mg/kg (14C)MX was administered to Wistar rats and radioactivity was determined in tissues after 2 and 6 hr. After 2 hr, the highest amount of radioactivity was detected in kidneys, followed by the stomach, ileum, urinary bladder and liver. At 6 hr, the concentration of radioactivity was markedly decreased in kidneys and urinary bladder and to a lesser extent in the gastrointestinal tract.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮（MX）在大鼠尿液中的排泄 ... 在雄性Wistar大鼠中进行了评估 ... 通过灌胃方式给予去离子水中的剂量，剂量在200 mg/kg到600 mg/kg之间，每次给一只动物 ... 收集尿液使用代谢笼，在给药后长达72小时进行尿液中MX的化学分析。 ... 只有0.03-0.07%的剂量（200 mg/kg或300 mg/kg）以完整MX的形式在尿液中排出...

... Excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) ... was evaluated in male Wistar rats ... dosed by gavage in deionized water at doses between 200 mg/kg and 600 mg/kg, for one animal at a time ... Urine was collected in metabolism cages up to 72 hr after dosing for chemical analysis of MX in urine. ... Only 0.03-0.07% of the dose (200 mg/kg or 300 mg/kg) was excreted in urine as intact MX...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T
• 危险类别码：
  R46
• 危险品运输编号：
  UN 2810
• RTECS号：
  LU3482000
• 海关编码：
  2932209090
• 包装等级：
  II
• 危险类别：
  6.1(a)
• 安全说明：
  S36/37/39,S45,S53
• 储存条件：
  库房应保持低温、通风和干燥的环境。

制备方法与用途

类别：有毒物质
毒性分级：高毒
急性毒性：

• 口服（小鼠）LD50：120毫克/公斤
• 皮肤（小鼠）LD50：130毫克/公斤

可燃性危险特性：可燃；火场释放有毒氯化物烟雾

储运特性：库房低温、通风、干燥

灭火剂：水、二氧化碳、干粉、砂土

反应信息

• 作为反应物：
  描述：

  3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以91%的产率得到3-chloro-4-(dichloromethyl)-5-methoxy-2,5-dihydrofuran-2-one
  参考文献：
  名称：

  Padmapriya, Abeysinghe A.; Just, George; Lewis, Norman G., Canadian Journal of Chemistry, 1985, vol. 63, p. 828 - 832

  摘要：

  DOI：
• 作为产物：
  描述：

  DL-酪氨酸 在 sodium hypochlorite 、 sodium chlorite 作用下， 以 水 为溶剂， 反应 48.0h， 生成 3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮
  参考文献：
  名称：

  Screening the precursors of strong mutagen [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] MX from chlorinated water

  摘要：

  DOI：

  10.1016/s0043-1354(99)00106-2

文献信息

• Identification of an Ethenoformyl Adduct Formed in the Reaction of the Potent Bacterial Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5<i>H</i>)-furanone with Guanosine
  作者：Tony Munter、Frank Le Curieux、Rainer Sjöholm、Leif Kronberg

  DOI：10.1021/tx9801514

  日期：1999.1.1

  water. In this study, we have reacted MX with guanosine, cytidine, thymidine, and calf thymus DNA in aqueous solutions. HPLC analyses of the reaction mixture of MX with guanosine showed that one main product peak was formed. In the reactions of MX with cytidine or thymidine, no product peaks representing base-modified nucleosides could be observed. The product from the MX guanosine reaction mixture was

  3-氯-4-（二氯甲基）-5-羟基-2（5H）-呋喃酮（MX）是一种有效的直接作用细菌诱变剂，是一种在氯消毒后的饮用水中产生的啮齿类致癌物。在这项研究中，我们使MX与鸟嘌呤，胞苷，胸苷和小牛胸腺DNA在水溶液中反应。MX与鸟苷的反应混合物的HPLC分析表明形成了一个主要产物峰。在MX与胞苷或胸苷的反应中，未观察到代表碱基修饰的核苷的产物峰。通过反相C18柱上的制备色谱分离MX鸟苷反应混合物中的产物，并通过紫外吸收，1H和13C NMR光谱以及质谱确定其结构。产物被鉴定为3-（β-D-呋喃呋喃糖基）-7-甲酰咪唑并[1,2-a]嘌呤-9（4H）-one（epsilonfGuo），在pH 7.4和37℃下进行反应的产率为约0.3mol％。在与MX反应的小牛胸腺DNA水解物中，在每10（7）个碱基中有五个加合物的检出限处，未观察到加合物。但是，这种失败并不排除在鼠伤寒沙门氏菌菌株TA100中观察
• Factors on the formation of strong mutagen [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] MX by chlorination of syringaldehyde
  作者：Yang Chengyong、Chen Zhuo、Zou Huixian、Lu Junhe、Zhang Jinqi

  DOI：10.1016/s0043-1354(00)00175-5

  日期：2000.12

  5-dimethoxybenzaldehyde) was chlorinated in the laboratory at different reaction time, temperature, pH and chlorine dose, and MX was determined and quantified by GC/MS. The finding suggests that the optimal chlorination conditions are as follows: temperature=298 K, pH=5, Cl:syrin. (mol:mol)=9:1. We also found that the formation of MX increased with the syringaldehyde concentration in a linear relationship

  摘要 在实验室对丁香醛（4-羟基-3,5-二甲氧基苯甲醛）在不同的反应时间、温度、pH值和氯剂量下进行氯化，并采用GC/MS对MX进行测定和定量。该发现表明，最佳氯化条件如下：温度=298 K，pH=5，Cl：syrin。(摩尔:摩尔)=9:1。我们还发现，MX 的形成随着丁香醛浓度的增加呈线性关系。此外，当丁香醛在碱性条件下用不同的氯剂量氯化时，没有检测到 MX。本研究将有助于阐明丁香醛生成MX的动力学过程，对更好地控制饮用水中的MX有很大帮助。
• Reaction of the Potent Bacterial Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5<i>H</i>)-furanone (MX) with 2‘-Deoxyadenosine and Calf Thymus DNA:  Identification of Fluorescent Propenoformyl Derivatives
  作者：Tony Munter、Frank Le Curieux、Rainer Sjöholm、Leif Kronberg

  DOI：10.1021/tx970195x

  日期：1998.3.1

  water disinfection byproduct 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was reacted with 2'-deoxyadenosine and calf thymus DNA in aqueous solutions at neutral conditions. HPLC analyses of the 2'-deoxyadenosine reaction mixtures showed that two previously unidentified products were formed. The products were isolated by preparative C18 chromatography, and their structures were characterized

  在中性条件下，将有效的细菌诱变剂和饮用水消毒副产物3-chloro-4-（dichloromethyl）-5-hydroxy-2（5H）-呋喃酮（MX）与2'-脱氧腺苷和小牛胸腺DNA反应。2'-脱氧腺苷反应混合物的HPLC分析表明，形成了两个先前未鉴定的产物。通过制备型C18色谱法分离产物，并通过UV吸收，荧光发射，1 H和13 C NMR光谱以及质谱对它们的结构进行表征。可以得出结论，在两种产品中，腺嘌呤单元的N-1和N6之间都形成了一个丙炔桥。在其中一种产品中，丙炔桥带有甲酰基[3-（2'-脱氧-β-D-呋喃呋喃糖基）-7H-8-甲酰基[2,1-i]嘧啶嘌呤++ +（pfA-dR）]，另一个取代基由甲酰基和氯原子[3-（2'-脱氧-β-D-呋喃呋喃糖基）-7H-8-甲酰基-9-氯[2,1-i]嘧啶嘌呤（ Cl-pfA-dR）]。这些新型加合物在可见光区域显示荧光，最大发射波长在460
• Anti-inflammatory botanical products for the treatment of metabolic syndrome and diabetes
  申请人：Metaproteomics, LLC

  公开号：EP2737897A2

  公开（公告）日：2014-06-04

  The present invention relates to compositions consisting essentially of a therapeutically effective amount of a compound selected from the group consisting of tetrahydro-isohumulone, tetrahydro-isocohumulone, and tetrahydro-isoadhumulone; and metformin, to be used in the treatment of an insulin related disorder, diabetes, obesity, or a cardiovascular disease.

  本发明涉及主要由治疗有效量的选自四氢-异胡麻酮、四氢-异胡麻酮和四氢-异胡麻酮组成的化合物和二甲双胍组成的组合物，用于治疗胰岛素相关疾病、糖尿病、肥胖症或心血管疾病。
• Negative selection and stringency modulation in continuous evolution systems
  申请人：President and Fellows of Harvard College

  公开号：US10179911B2

  公开（公告）日：2019-01-15

  Strategies, systems, methods, reagents, and kits for phage-assisted continuous evolution are provided herein. These include strategies, systems, methods, reagents, and kits allowing for stringency modulation to evolve weakly active or inactive biomolecule variants, negative selection of undesired properties, and/or positive selection of desired properties.

  本文提供了噬菌体辅助连续进化的策略、系统、方法、试剂和试剂盒。这些策略、系统、方法、试剂和试剂盒允许进行严格性调节，以进化出弱活性或无活性的生物分子变体，对不需要的特性进行负选择，和/或对需要的特性进行正选择。

表征谱图