烟曲酶毒素 C | 118974-02-0

• 物质功能分类: 天然产物 - 生物碱
• 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 C
• 中文别名: 烟曲霉素C,来源于烟曲霉菌；烟曲酶毒素C；烟曲霉毒素c；烟曲霉素C；烟曲霉震颤素C；烟曲霉毒素C
• 英文名称: fumitremorgin C
• 英文别名: FTC；12α-fumitremorgin C；(1S,12S,15S)-7-methoxy-12-(2-methylprop-1-enyl)-10,13,19-triazapentacyclo[11.7.0.03,11.04,9.015,19]icosa-3(11),4(9),5,7-tetraene-14,20-dione
• CAS: 118974-02-0
• 化学式: C₂₂H₂₅N₃O₃
• 分子量: 379.459
• InChiKey: DBEYVIGIPJSTOR-FHWLQOOXSA-N

物化性质

• 熔点：
  259.5-260.5℃
• 沸点：
  642.9±55.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)
• 溶解度：
  乙腈：可溶5 mg/mL
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  65.6
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

毒理性

• 毒性总结

Fumitremorgin C 抑制 ATP 结合盒转运蛋白 (ABCG2)，也称为乳腺癌耐药蛋白。ABCG2 以赋予多药耐药性以及影响不同药物的生物利用度而闻名。因此，fumitremorgin C 常用于提高癌症患者对化疗药物的敏感性。致震颤性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，以及抑制 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 诱导的氯电流，然后导致突触中神经递质水平的降低。

Fumitremorgin C inhibits ATP-binding cassette transporter (ACBG2), also known as breast cancer resistance protein. ACBG2 is known to confer multidrug resistance and also affects the bioavailability of different drugs. Thus fumitremorgin C is often used to sensitize cancer patients to chemotherapeutic drugs. 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, A3027)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

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

震颤原真菌毒素影响中枢神经系统活动。它们会导致牛患有一种被称为“蹒跚综合症”的神经疾病。

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）。

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

震颤原真菌毒素影响中枢神经系统活动，诱导神经症状，包括精神混乱、瘫痪、震颤、癫痫和死亡。它们导致牛患有一种被称为“蹒跚综合症”的神经疾病，其特征是肌肉震颤和过度兴奋。

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. (A2976)

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3

制备方法与用途

背景

烟曲霉毒素是由串珠镰刀菌（Fusarium moniliforme）产生，通常在霉变的玉米中发现，真菌毒素。烟曲霉毒素发现较晚，最早于1988年报告，最常见的是烟曲霉毒素B、烟曲霉毒素C。

生物活性

Fumitremorgin C是有效，选择性的ABCG2/BRCP抑制剂。

体外研究

Multidrug resistance (MDR) is a major problem in cancer chemotherapy. Fumitremorgin C is extremely effective in reversing resistance to mitoxantrone, doxorubicin, and topotecan in multidrug-selected cell lines. In MCF-7/mtxR (a mitoxantroneselected cell line), fumitremorgin C reverses mitoxantrone resistance (114-fold) and doxorubicin resistance (3-fold). Fumitremorgin C (5/AM)significantly potentiates the toxicity of mitoxantrone (93-fold), doxorubicin (26-fold), and topotecan (24-fold) in S1M1-3.2 cells. Reversal of resistance is associated with an increase in drug accumulation. Fumitremorgin C does not reverse drug resistance in cells with elevated expression of Pgp or MRP. Fumitremorgin C almost completely reverses resistance mediated by BCRP in vitro and is a pharmacological probe for the expression and molecular action of this transporter. Fumitremorgin C also enhances the toxicity of mitoxantrone and topotecan in vector-transfected MCF-7 cells (2.5–5.6 fold). It reduces the IC ₅₀ of topotecan in BCRP-overexpressing cells below that observed in the untreated vector-transfected cells. .

反应信息

• 作为反应物：
  描述：

  烟曲酶毒素 C 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以82%的产率得到12β-fumitremorgin C
  参考文献：
  名称：

  A synthesis of so-called fumitremorgin C

  摘要：

  DOI：

  10.1016/s0040-4020(01)80057-0
• 作为产物：
  描述：

  ethyl 1-(2-hydroxy-2-methylpropyl)-7-methoxy-2-((S)-1-((2,2,2-trichloroethoxy)carbonyl)pyrrolidine-2-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 在 氯化亚砜 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 锌 作用下， 以 氯仿 为溶剂， 反应 48.0h， 生成 烟曲酶毒素 C
  参考文献：
  名称：

  （-）-Fumitremorgin C的第一个全合成

  摘要：

  介绍了使用6-甲氧基-N-羟基色氨酸（5a）的震颤性呋喃菌素C（1a）的第一个全合成。我们的方法的特征是形成硝酮（6a），立体选择性环加成生成7a，开环并与L-脯氨酸衍生物偶合以形成14。碱催化的差向异构化得到16，通过脱保护胺将其转化为标题化合物功能，二氧哌嗪的形成和脱水。

  DOI：

  10.1016/s0040-4020(01)90342-4

文献信息

• Reversal of multidrug resistance in human colon carcinoma cells
  申请人：Rabindran Sridhar Krishna

  公开号：US06878737B2

  公开（公告）日：2005-04-12

  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fumitremorgin A，B和C以及公式（I）一系列二酮哌嗪来重新敏感化多药耐药（MDR）癌细胞，以增强化疗药物的细胞毒性作用。
• Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in<i>Aspergillus fumigatus</i>
  作者：Naoki Kato、Hirokazu Suzuki、Hiroshi Takagi、Yukihiro Asami、Hideaki Kakeya、Masakazu Uramoto、Takeo Usui、Shunji Takahashi、Yoshikazu Sugimoto、Hiroyuki Osada

  DOI：10.1002/cbic.200800787

  日期：2009.3.23

  Missing links in the fumitremorgin biosynthetic pathway have been elucidated as 1) hydroxylation of the tryprostatin B indole ring at C‐6 by FtmC, 2) CN bond formation by FtmE to produce fumitremorgin C, and 3) the subsequent dihydroxylation of fumitremorgin C by FtmG to afford fumitremorgin B. These are also crucial processes for the inhibitory activity of fumitremorgin C against breast cancer resistance

  缺失的链接在烟曲霉毒素生物合成途径已被鉴定为1）在C-6通过FtmC，2）C的tryprostatin乙吲哚环的羟基化 N键的形成通过FtmE以产生烟曲霉毒素C，以及3）烟曲霉毒素C的后续二羟基化这些也是Fumitremorgin C对乳腺癌抗性蛋白（BCRP）的抑制活性的关键过程。
• Synthesis of the Multidrug Reversal Agent Ko143 and Its Parent Natural Product Fumitremorgin C
  作者：Melanie Zechner、Karl‐Heinz Altmann

  DOI：10.1002/hlca.202200171

  日期：2023.2

  6-methoxy-l-tryptophan methyl ester from Cbz-l-aspartic acid methyl ester, m-anisidine and differently substituted benzaldehydes. With p-nitrobenzaldehyde as one of the starting materials, this route gave access to 6-methoxy-l-tryptophan methyl ester in five steps and 20 % overall yield; however, it is less efficient than a previously reported synthesis of 6-methoxy-l-tryptophan methyl ester from 6-methoxy indole

  Ko143 是真菌代谢物 fumitremorgin C 的四环合成类似物。Ko143 是膜结合外排转运蛋白 ABCG2 的强效特异性抑制剂，可逆转癌细胞中 ABCG2 介导的耐药性。在这里，我们描述了 Ko143 的改进合成，它依赖于在Bischler – Napieralski反应中形成的亚胺的高选择性、底物控制还原，与衍生自 6-甲氧基-l-色氨酸甲酯和异戊酸的酰胺关键一步。我们还开发了一条从Cbz- l -天冬氨酸甲酯、间茴香胺和不同取代的苯甲醛制备6-甲氧基- l -色氨酸甲酯的新路线。和该路线以对硝基苯甲醛为起始原料，分五步得到6-甲氧基-1-色氨酸甲酯，总收率为20%；然而，它的效率低于先前报道的从 6-甲氧基吲哚合成 6-甲氧基-1-色氨酸甲酯的效率。
• He, Haiyin; Rabindran, Sridhar G.; Greenberger, Lee M., Medicinal Chemistry Research, 1999, vol. 9, # 6, p. 424 - 437
  作者：He, Haiyin、Rabindran, Sridhar G.、Greenberger, Lee M.、Carter, Guy T.

  DOI：——

  日期：——
• Antibacterial activity of diketopiperazines isolated from a marine fungus using t-butoxycarbonyl group as a simple tool for purification
  作者：Bahaa El-Dien M. El-Gendy、Mostafa E. Rateb

  DOI：10.1016/j.bmcl.2015.06.010

  日期：2015.8

  Nine diketopiperazines were characterized from the culture of marine fungal isolate MR2012 which based on DNA amplification and sequencing of the fungal internal transcribed spacer (ITS) region was identified as Aspergillus fumigatus. The isolated fungal metabolites 4-12 were unambiguously identified as a series of simple and re-arranged diketopiperazines by analysis of spectroscopic data. t-Butoxycarbonyl group (BOC) derivatization was used to separate the intractable mixture of 4 and 5. When all compounds were evaluated for antimicrobial activity against gram positive bacteria, the isolated metabolites showed moderate to weak effects, while the semisynthetic derivatives 4a and 5a displayed strong activity comparable to the positive control, tetracycline against gram positive bacteria. (C) 2015 Elsevier Ltd. All rights reserved.