烟曲酶毒素A | 12626-18-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 烟曲酶毒素A
• 英文名称: Fumitremorgin A
• 英文别名: (5R,10S,10aR,14aS,15bS)-10a-hydroxy-7-methoxy-2,2-dimethyl-10-((3-methylbut-2-en-1-yl)oxy)-5-(2-methylprop-1-en-1-yl)-1,10,10a,12,13,14,14a,15b-octahydro-5H,15H-3,4-dioxa-5a,11a,15a-triazacycloocta[lm]indeno[5,6-b]fluorene-11,15(2H)-dione；(10aR)-10a-hydroxy-7-methoxy-2,2-dimethyl-10c-(3-methyl-but-2-enyloxy)-5c-(2-methyl-propenyl)-(10ar,14ac,15bc)-1,10,10a,12,13,14,14a,15b-octahydro-2H-3,4-dioxa-5a,11a,15a-triaza-cycloocta[lm]indeno[5,6-b]fluorene-11,15-dione；O¹³-(3-methyl-but-1-enyl)-verruculogen；@fumitremorgin-A；(9R,14S,17S,23R,24S)-23-hydroxy-5-methoxy-12,12-dimethyl-24-(3-methylbut-2-enoxy)-9-(2-methylprop-1-enyl)-10,11-dioxa-8,15,21-triazahexacyclo[12.10.1.02,7.08,25.015,23.017,21]pentacosa-1(25),2(7),3,5-tetraene-16,22-dione
• CAS: 12626-18-5
• 化学式: C₃₂H₄₁N₃O₇
• 分子量: 579.693
• InChiKey: ACGHJVZDNQZJOV-BMOJZYMJSA-N

物化性质

• 沸点：
  762.1±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  42
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

毒理性

• 毒性总结

震颤素类真菌毒素通过干扰神经递质的释放来发挥其毒性作用，可能是通过导致神经末梢的变性。它们被认为可以抑制γ-氨基丁酸（GABA）受体，包括突触前和突触后的，同时还可以抑制GABA-T受体上的递质分解。这最初会增加神经递质的水平，增强GABA诱导的氯离子电流，然后导致突触中神经递质水平的降低。

Tremorgenic mycotoxins exert their toxic effects by interfering with neurotransmitter release, possibly by causing degeneration of nerve terminals. They are thought to inhibit gamma-aminobutyric acid (GABA) receptors, both pre- and postsynaptic, as well as inhibit transmitter breakdown at the GABA-T receptors. This would initially increase neurotransmitter levels, potentiating the GABA-induced chloride current, then lead to decreased levels of neurotransmitter in the synapse. (A2974, A2975, A2976)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

震颤素类真菌毒素影响中枢神经系统活动。它们会导致牛患上一种被称为“蹒跚综合症”的神经系统疾病。

Tremorgenic mycotoxins affect central nervous system activity. They cause a neurological disease of cattle known as "staggers syndrome". (A2976)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服、皮肤、吸入和 parenteral（被污染的药物）。 (A3101)

Oral, dermal, inhalation, and parenteral (contaminated drugs). (A3101)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

震颤素类真菌毒素影响中枢神经系统活动，引起包括精神混乱、瘫痪、震颤、惊厥和死亡在内的神经症状。它们会导致牛患有一种被称为“摇摆综合症”的神经疾病，其特征是肌肉震颤和过度兴奋。研究还表明，接触烟曲霉A会引起心动过缓、心律不齐和高血压。

Tremorgenic mycotoxins affect central nervous system activity, inducing neurologic symptoms including mental confusion, paralysis, tremors, seizures, and death. They cause a neurological disease of cattle known as "staggers syndrome", which is characterized by muscle tremors and hyperexcitability. Fumitremorgin A exposure has also been shown to cause bradycardia, arrhythmia, and hypertension. (A2974, A3025)

来源:Toxin and Toxin Target Database (T3DB)

反应信息

• 作为反应物：
  描述：

  烟曲酶毒素A 在 platinum(IV) oxide 硫酸 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 生成 (1S,2S,12S,15S)-12-(2-hydroxy-2-methylpropyl)-1,2,7-trimethoxy-10,13,19-triazapentacyclo[11.7.0.03,11.04,9.015,19]icosa-3(11),4(9),5,7-tetraene-14,20-dione
  参考文献：
  名称：

  Chemistry of tremorogenic metabolites. I. Fumitremorgin a from Aspergillus fumigatus.

  摘要：

  从曲霉菌中分离出了两种新的吲哚代谢物--烟曲霉毒素 A 和 B。这两种代谢物会导致实验动物严重震颤和抽搐。主要根据该化合物及其一些衍生物的光谱数据，确定了 fumitremorgin A 的结构（包括立体化学结构）为 1。本文讨论了影响烟曲霉毒素 A 和相关化合物出现致震活性的立体化学因素。

  DOI：

  10.1248/cpb.28.245
• 作为产物：
  描述：

  ((4,4-diethoxy-2-methylbutan-2-yl)peroxy)triethylsilane 在 N-甲基吗啉 、 咪唑 、 四氧化锇 、 三氟化硼乙醚 、 四丁基氟化铵 、 氯化锆(IV) 、 四丁基碘化铵 、 二正丁基氧化锡 、 碳酸氢钠 、 溶剂黄146 、 二乙胺 、 亚硝基苯 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 、 叔丁醇 为溶剂， 反应 65.42h， 生成 烟曲酶毒素A
  参考文献：
  名称：

  Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C–H Borylation

  摘要：

  Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.

  DOI：

  10.1021/jacs.5b07154

文献信息

• MITHRAMYCIN DERIVATIVES HAVING INCREASED SELECTIVITY AND ANTI-CANCER ACTIVITY
  申请人：University of Kentucky Research Foundation

  公开号：US20190083519A1

  公开（公告）日：2019-03-21

  Mithramycin side chain carboxylic acid (MTM-SA) derivative are provided, which include a substituted amino acid derivative, a substituted amino acid dipeptide derivative, or an unsubstituted dipeptide derivative. The MTM-SA derivatives are useful for treatment of cancer or neuro-diseases associated with an aberrant erythroblast transformation-specific transcription factor. Unique MTM-SA derivatives have increased selectively toward ETS transcription factor.

  米司麦霉素侧链羧酸（MTM-SA）衍生物包括一种取代氨基酸衍生物、一种取代氨基酸二肽衍生物或一种未取代的二肽衍生物。这些MTM-SA衍生物对于治疗与异常红细胞转化特异性转录因子相关的癌症或神经疾病很有用。独特的MTM-SA衍生物对ETS转录因子具有增强的选择性。
• MITHRAMYCIN OXIME AND HYDRAZINE DERIVATIVES HAVING INCREASED SELECTIVITY AND ANTI-CANCER ACTIVITY
  申请人：University of Kentucky Research Foundation

  公开号：US20200131218A1

  公开（公告）日：2020-04-30

  Compounds described herein are mithramycin (MTM) oxide (OX) derivatives and MTM Hydrazine (HY) derivatives. These compounds are useful for treatment of cancers and neuro-diseases.

  本文描述的化合物是米司雷霉素（MTM）氧化物（OX）衍生物和MTM肼（HY）衍生物。这些化合物对于治疗癌症和神经疾病非常有用。
• Reversal of multidrug resistance in human colon carcinoma cells
  申请人：American Cyanamid Comany

  公开号：US20020169111A1

  公开（公告）日：2002-11-14

  The present invention describes the use of fumitremorgin A, B and C and a series of diketopiperazines of Formula (I) to resensitize multidrug resistant (MDR) cancer cells to the cytotoxic effects of chemotherapeutic drugs.

  本发明描述了利用富马酰菌素A，B和C以及一系列式（I）的二酮肽来使多药耐药（MDR）癌细胞重新对化疗药物的细胞毒性效应产生敏感。
• Identification of the Verruculogen Prenyltransferase FtmPT3 by a Combination of Chemical, Bioinformatic and Biochemical Approaches
  作者：Kathrin Mundt、Beate Wollinsky、Han-Li Ruan、Tianjiao Zhu、Shu-Ming Li

  DOI：10.1002/cbic.201200523

  日期：2012.11.26

  Spectacular identification: Conversion of verruculogen to fumitremorgin A was demonstrated biochemically with a recombinant O‐prenyltransferase, FtmPT3. The responsible gene was not located within the previously identified fumitremorgin gene cluster in N. fischeri NRRL181.

  眼镜鉴定：用重组O异戊二烯基转移酶FtmPT3生化证明了维库菌原转化为femotremorginA。负责任的基因不在费希尔猪笼草NRRL181中先前鉴定的fumitremorgin基因簇内。
• Compositions to improve the therapeutic benefit of bisantrene and analogs and derivatives thereof
  申请人：Race Oncology Ltd.

  公开号：US10548876B2

  公开（公告）日：2020-02-04

  The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to bisantrene or derivatives, analogs, or prodrugs thereof.

  本发明描述了通过提高单一疗法的疗效或减少副作用来改善以前因治疗效果不理想而受到限制的治疗剂的疗效的方法和组合物。这些方法和组合物尤其适用于双蒽或其衍生物、类似物或原药。