(3alpha,4beta,8alpha)-4,15-Bis(acetyloxy)-3-hydroxy-12,13-epoxytrichothec-9-en-8-yl 3-methylbutanoate | 21259-20-1

• 物质功能分类: 分析化学 - 标准品 - 食品和化妆品标准品
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (3alpha,4beta,8alpha)-4,15-Bis(acetyloxy)-3-hydroxy-12,13-epoxytrichothec-9-en-8-yl 3-methylbutanoate
• 英文别名: [(1S,2R,4S,7R,9R,10R,11S)-11-acetyloxy-2-(acetyloxymethyl)-10-hydroxy-1,5-dimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-4-yl] 3-methylbutanoate
• CAS: 21259-20-1
• 化学式: C₂₄H₃₄O₉
• 分子量: 466.5
• InChiKey: BXFOFFBJRFZBQZ-GOLADLMOSA-N

物化性质

• 熔点：
  151.5℃
• 比旋光度：
  D26 +15° (c = 2.58 in ethanol)
• 沸点：
  489.35°C (rough estimate)
• 密度：
  1.1942 (rough estimate)
• 闪点：
  2 °C
• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL； DMSO:PBS(pH7.2)(1:1)：0.5mg/ml；乙醇：20mg/mL
• 颜色/状态：
  White needles from benzene & Skellysolve B; acetate deriv: amorphous solid from ether & pentane
• 蒸汽压力：
  3.06X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable in the solid form

• 旋光度：
  Specific optical rotation: (c = 2.58 in ethanol): +15 °C at 26 °C/D
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  9

ADMET

代谢

给予一头哺乳期母牛口服180毫克T-2毒素后，从其尿液中获得了两种主要代谢物。它们是3'-羟基-HT 2毒素和3'-羟基T 2毒素。

Two major metabolites were obtained from the urine of a lactating cow given 180 mg of T-2 toxin orally. They were 3'-hydroxy-HT 2 toxin & 3'-hydroxy T 2 toxin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

人类肝脏酶将T2-三线镰刀菌毒素脱乙酰化成HT2-三线镰刀菌毒素。

Human liver enzymes deacetylate T2-trichothecene to HT2-trichothecene in vitro.

来源:Hazardous Substances Data Bank (HSDB)

代谢

口服给予小鼠和大鼠(3)H-T2-三线霉素(1 mg/kg体重)的放射性,在72小时内通过粪便(55%)和尿液(15%)排出。...分析大鼠粪便中回收的放射性,发现2.7%的剂量以未改变的T2-三线霉素形式排出,7.5%以4-O-脱乙酰化T2-三线霉素(HT2-三线霉素)形式排出。...剩余的粪便排泄产物未被鉴定。在尿液中,HT2-三线霉素占总剂量的1.4%,8-羟基二乙酰氧基斯卡波醇(1.8%)被鉴定;还分离出3种未鉴定的代谢物。...环氧化合物基团...似乎是毒理学活性的关键;肝脏通过环氧水合酶来解毒T2-三线霉素。在体外,大鼠肝脏匀浆将T2-三线霉素代谢为HT2-三线霉素、T2-三线霉素四醇、4-脱乙酰新茄病醇。...和新生茄病醇。...从HT2-三线霉素中也获得了相同的代谢物,表明T2-三线霉素优先在C-4位置水解生成NT2-三线霉素。

The radioactivity of orally admin (3)H-T2-trichothecene (1 mg/kg body wt) to mice & rats was recovered in feces (55%) & urine (15%) within 72 hr. ... Analysis of the radioactivity recovered in feces of rats revealed that 2.7% of the dose was excreted as unchanged T2-trichothecene & 7.5% as 4-O-deacetylated T2-trichothecene (HT2-trichothecene)...the remaining fecal excretion products were not identified. In urine, HT2-trichothecene, representing 1.4% of the total dose & 8-hydroxydiacetoxyscirpenol (1.8%) were identified; 3 unidentified metabolites...were also isolated. The epoxide moeity...seems to be essential for its toxicological activity; the liver detoxifies T2-trichothecene, probably through epoxide hydrolase. In vitro, rat liver homogenate metabolizes T2-trichothecene to HT2-trichothecene, T2-trichothecene tetraol, 4-deacetylneosolaniol...& neosolaniol... The same metabolites were obtained from HT2-trichothecene, indicating that T2-trichothecene was preferentially hydrolyzed at the C-4 position to give NT2-trichothecene.

来源:Hazardous Substances Data Bank (HSDB)

代谢

曲霉菌属产生的三环烯类是倍半萜类毒素。由于这些霉菌毒素非常稳定，因此对微生物转化产生了兴趣，这些转化能够去除被污染的谷物或谷物产品中的毒素。对23种酵母菌进行了测试，这些酵母菌被归类为毛霉科（子囊菌门，子囊菌亚门），包括四种毛霉科物种和19种目前归类在Blastobotrys中的无性型物种，以测试它们将三环烯T-2毒素转化为毒性较低产品的能力。这些物种产生了三种生物转化类型：乙酰化形成3-乙酰T-2毒素，糖基化形成T-2毒素3-葡萄糖苷，以及去除异戊酰基团形成新长春花醇。有些物种产生了多种生物转化类型。三种Blastobotrys物种将T-2毒素转化为T-2毒素3-葡萄糖苷，这是一种在被曲霉感染的谷物中已被识别为隐匿性霉菌毒素的化合物。这是关于微生物全细胞方法生产三环烯糖苷的首份报告，T-2毒素3-葡萄糖苷的大量可用性将促进毒性测试和开发检测农业和其他产品中这种化合物的方法。

Trichothecenes are sesquiterpenoid toxins produced by Fusarium species. Since these mycotoxins are very stable, there is interest in microbial transformations that can remove toxins from contaminated grain or cereal products. Twenty-three yeast species assigned to the Trichomonascus clade (Saccharomycotina, Ascomycota), including four Trichomonascus species and 19 anamorphic species presently classified in Blastobotrys, were tested for their ability to convert the trichothecene T-2 toxin to less-toxic products. These species gave three types of biotransformations: acetylation to 3-acetyl T-2 toxin, glycosylation to T-2 toxin 3-glucoside, and removal of the isovaleryl group to form neosolaniol. Some species gave more than one type of biotransformation. Three Blastobotrys species converted T-2 toxin into T-2 toxin 3-glucoside, a compound that has been identified as a masked mycotoxin in Fusarium-infected grain. This is the first report of a microbial whole-cell method for producing trichothecene glycosides, and the potential large-scale availability of T-2 toxin 3-glucoside will facilitate toxicity testing and development of methods for detection of this compound in agricultural and other products.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

评估：没有关于来自串珠镰刀菌的毒素对人类致癌性的数据。T-2毒素在实验动物中的致癌性有有限证据。总体评估：来自串珠镰刀菌的毒素对人类的致癌性无法分类（第3组）。

Evaluation: No data were available on the carcinogenicity to humans of toxins derived from Fusarium sporotrichioides. There is limited evidence in experimental animals for the carcinogenicity of T-2 toxin. Overall evaluation: Toxins derived from Fusarium sporotrichiodes are not classifiable as to their carcinogenicity to humans (Group 3).

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物：T2-三线镰孢霉毒素

IARC Carcinogenic Agent:T2-Trichothecene

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：第3组：对其对人类的致癌性无法分类

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity 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论：第31卷（1983年）一些食品添加剂、饲料添加剂和天然存在物质

IARC Monographs:Volume 31: (1983) Some Food Additives, Feed Additives and Naturally Occurring Substances

来源:International Agency for Research on Cancer (IARC)

毒理性

• 副作用

Dermatotoxin - 皮肤烧伤。

Dermatotoxin - Skin burns.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

吸收、分配和排泄

T2-三嗪烯能轻易通过猪和鼠的皮肤和肠道被吸收。

T2-Trichothecene is readily absorbed through skin & the gut in pigs & rats.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

T-2毒素会通过哺乳期牛和猪的乳汁传播。

T-2 toxin is transmitted in the milk in lactating cattle & pigs.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

估计每天口服1毫克/千克体重的T-2毒素，连续8天的鸡所产的蛋，相当于饮食中含有的1.6毫克/千克T-2毒素，含有0.9微克此物质。

Estimated that the eggs from chickens treated orally with 1 mg T-2 toxin/kg body weight daily for 8 consecutive days, which is equivalent to 1.6 mg/kg dietary T-2, contain 0.9 ug of this material.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给予小鼠和大鼠(3)H-T2-三环素(1 mg/kg体重)后，其放射性在72小时内以粪便(55%)和尿液(15%)的形式回收。它分布在肝脏、肾脏和其他器官中，没有特定的积累。

The radioactivity of orally admin (3)H-T2-trichothecene (1 mg/kg body wt) to mice & rats was recovered in feces (55%) & urine (15%) within 72 hr. It was distributed in the liver, kidneys & other organs, without specific accumulation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-T-2毒素口服给予小鼠和大鼠后，迅速分布到组织中，并通过粪便和尿液排出。口服给药后，小鼠血浆中放射性标记物含量在30分钟内达到最大值……，而豚鼠在肌肉注射后……也达到最大值。在通过饲料给予(3)H-T-2毒素的雏鸡中，血液、血浆、腹脂、心脏、肾脏、肌胃、肝脏和剩余胴体中的最大水平在4小时内达到，而肌肉、皮肤、胆汁和胆囊中的最大水平在12小时内达到……。T-2毒素在猪组织中的分布与鸡相似……。

(3)H-T-2 Toxin given orally to mice and rats was distributed rapidly to tissues and eliminated in feces and urine. Maximal levels of radiolabel were found after 30 min in plasma of mice after oral administration ... and of guinea pigs after intramuscular injection ... . In chicks administered (3)H-T-2 toxin in the diet, maximal levels were reached by 4 hr in blood, plasma, abdominal fat, heart, kidneys, gizzard, liver and the remainder of the carcass and by 12 hr in muscle, skin, bile and gall bladder ... . The distribution of T-2 toxin in tissues of swine was similar to that in chickens ... .

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  Xn,T+,F,T
• 安全说明：
  S16,S22,S26,S28,S36,S36/37,S36/37/39,S45
• 危险类别码：
  R20/21/22,R38,R36,R26/27/28,R11
• WGK Germany：
  3
• 海关编码：
  29329990
• 危险品运输编号：
  UN 3462 6.1/PG 1
• 包装等级：
  I
• 危险类别：
  6.1(a)

制备方法与用途

概述

T-2毒素是由镰刀菌产生的A类单端孢霉烯族真菌毒素中毒性最强的一种，对人畜危害较大。它广泛分布于全球各地的玉米和小麦田间作物以及库存谷物中，并在1973年被联合国粮农组织（FAO）和世界卫生组织（WHO）列为天然存在的危险食品污染毒物之一。

性质

T-2毒素是一种四环倍半萜烯化合物，化学名为4β-15-二乙酰氧基-3α-羟基-8α-(3-甲基丁酰氧)-12,13-环氧单端孢霉-9-烯，分子式为C₂₄H₃₄O₉。该毒素性质稳定，在食物生产和加工过程中不易被高压灭菌灭活。需在200～210℃下灭菌30～40分钟或浸泡于NaClO-NaOH溶液中至少4小时才能灭活。一些真菌和酶可以改变并去除T-2毒素的毒性，而环氧环和双键被认为是主要的毒性基团。

生物活性

T-2毒素（T-2 Mycotoxin）是由各种镰刀菌种产生的真菌毒素，在小鼠和大鼠中的半数致死量分别为5.2 mg/kg BWa和1.5 mg/kg BWa。在动物体内，T-2毒素可以转化为多种代谢产物，如HT-2毒素和T-2-triol，这些均为水解产物。

该毒素作为抑制肽基转移酶（60s核糖体亚基）结合及蛋白质合成的抑制剂，在DNA和RNA的合成、磷脂代谢方面干扰，并增加肝脏中脂质过氧化物的水平。此外，它还能在免疫系统、胃肠道组织以及胎儿组织中诱导细胞凋亡。

文献信息

• [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] 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）。
• [EN] HETEROCYCLIC LSF INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE LSF HÉTÉROCYCLES ET LEURS UTILISATIONS
  申请人：UNIV BOSTON

  公开号：WO2021150835A1

  公开（公告）日：2021-07-29

  The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.

  本发明涉及杂环SV40因子（LSF）抑制剂及其用途。在某些实施例中，本发明揭示了化合物的分子式（I）。在某些实施例中，分子式（I）的化合物用于抑制受试者中的LSF。在某些实施例中，分子式（I）的化合物用于治疗受试者中的癌症。