(2E,3E,5E,7E,9E)-2-亚乙基-11-[(1R,2S,5R)-2-羟基-2-(2-羟基乙基)-4-氧代-6-氧杂-3-氮杂双环[3.1.0]己烷-5-基]-4,6,10-三甲基-11-氧代十一碳-3,5,7,9-四烯酸甲酯 | 79748-81-5

• 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
• 中文名称: (2E,3E,5E,7E,9E)-2-亚乙基-11-[(1R,2S,5R)-2-羟基-2-(2-羟基乙基)-4-氧代-6-氧杂-3-氮杂双环[3.1.0]己烷-5-基]-4,6,10-三甲基-11-氧代十一碳-3,5,7,9-四烯酸甲酯
• 英文名称: fusarin C
• 英文别名: methyl (2E,3E,5E,7E,9E)-2-ethylidene-11-[(1R,4S,5R)-4-hydroxy-4-(2-hydroxyethyl)-2-oxo-6-oxa-3-azabicyclo[3.1.0]hexan-1-yl]-4,6,10-trimethyl-11-oxoundeca-3,5,7,9-tetraenoate
• CAS: 79748-81-5
• 化学式: C₂₃H₂₉NO₇
• 分子量: 431.486
• InChiKey: FZFYFSUIOSWLHW-UNZVFGKVSA-N

物化性质

• LogP：
  2.050 (est)
• 颜色/状态：
  Yellow oil
• 溶解度：
  Soluble in ethanol and methanol.
• 旋光度：
  Specific optical rotation at 23 °C for D (sodium) line = +47.04 deg (2 percent in methanol).

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

两种大鼠肝微粒体酶，羧酸酯酶和单加氧酶，参与真菌毒素C的代谢。羧酸酯酶催化真菌毒素C转化为水溶性的真菌毒素PM1。真菌毒素C转化为活性致突变代谢物的工作由单加氧酶催化。有人提出，酯酶将真菌毒素C代谢为致突变性较低的形式：通过用酯酶抑制剂（1 uM 二异丙基氟磷酸）预处理微粒体，真菌毒素C对鼠伤寒沙门氏菌TA100的致突变性可以加倍。

Two rat liver microsomal enzymes, carboxylesterase and a monooxygenase, are involved in the metabolism of fusarin C. The carboxyesterase catalyses the converstion of fusarin C to the water-soluble fusarin PM1. The conversion of fusarin C to an active mutagenic metabolite(s) is catalysed by a monooxygenase. It has been suggested that esterases metabolize fusarin C to a less mutagenic form: the mutagenicity of fusarin C to Salmonella typhimurium TA100 could be doubled by pretreating the microsomes with an esterase inhibitor (1 uM diisopropyl fluorophosphate).

来源:Hazardous Substances Data Bank (HSDB)

代谢

FC（Fusarin C）是由镰刀菌产生的代谢物，在微粒体激活下具有基因毒性。通过使用由苯巴比妥诱导的大鼠肝脏微粒体混合物建立的体外代谢激活系统，已经分离出FC的两个代谢物，即fusarin Z（FZ）和fusarin X（FX），并鉴定了它们的化学结构。在Ames试验中，FZ和FX的致突变性分别是FC的500倍和60倍。两者都是在FC的1位上进行羟基化反应产生的。FZ是一个涉及2,3-双键异构化和21-甲基酯与新生成的1-羟基基团之间分子内转酯化的伽马-内酯。然而，FX不能通过微粒体系统转化为FZ。

Fusarin C (FC), a metabolite formed by Fusarium moniliforme, is, with microsomal activation, genotoxic. Two metabolites of FC, fusarin Z (FZ) and fusarin X (FX), have been isolated from an in vitro metabolic activation system using microsomal mixtures from phenobarbital-induced rat livers and their chemical structures identified. FZ and FX are 500 and 60 times more mutagenic than FC in the Ames test, respectively. Both result from hydroxylation at the 1-position of FC. FZ is a gamma-lactone involving isomerization of the 2,3-double bond and intramolecular transesterification between the 21-methyl ester and the newly formed 1-hydroxyl group. FX, however, could not be converted to FZ by the microsomal system.

来源:Hazardous Substances Data Bank (HSDB)

代谢

FC（Fusarin C）是一种强大的诱变剂，存在于被Fusarium moniliforme（串珠镰刀菌）污染的玉米中。这种化合物需要代谢激活，其中用苯巴比妥诱导的大鼠微粒体最为有效。抑制同时诱导的酯酶活性，后者产生了一个诱变性较小的代谢物，使FC的诱变性加倍。一氧化碳抑制了FC的诱变性，这表明涉及含血红素的酶。然而，针对苯巴比妥诱导的细胞色素P-450酶PB-4和PB-5的单克隆抗体，虽然抑制了对硝基茴香醚和黄曲霉毒素B1诱变性的O-脱甲基化，但对FC的诱变性没有影响。这意味着这些酶要么不参与FC的激活，要么FC与抗体对细胞色素P-450酶的结合竞争得很好。还检测到了FC的两个额外的代谢物。其中一个的紫外光谱与FC相似；另一个在326 nm处有最大吸收波长，并且其在反相高效液相色谱上的保留时间对pH的变化非常敏感。

Fusarin C (FC) is a potent mutagen present on Fusarium moniliforme contaminated corn. This compound requires metabolic activation for which microsomes from phenobarbital-induced rats are most effective. Inhibition of the simultaneously induced esterase activity, which produced a less mutagenic metabolite, doubled the mutagenicity of FC. Carbon monoxide inhibited the mutagenicity of FC, suggesting the involvement of a heme containing enzyme. However, monoclonal antibodies specific for the phenobarbital-induced cytochrome P-450 enzymes PB-4 and PB-5, while inhibiting O-demethylation of p-nitroanisole and aflatoxin B1 mutagenicity, had not effect on FC mutagenicity. This implies that either these enzymes are not involved in the activation of FC or FC competes well with the antibodies for binding to the cytochrome P-450 enzymes. Two additional metabolites of FC were detected. One had an ultraviolet spectrum similar to FC: the other had a lambda max at 326 nm, and its retention time on reverse phase HPLC was very sensitive to changes in pH.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在本研究中，报告了3H-杂色曲霉素C（3H-FC）在大鼠体内的分布与消除，以及FC在大鼠食管培养组织的DNA结合情况。放射性物质在大鼠组织中的分布会动态变化，在将3H-FC注入大鼠胃中后，肠道、胃和肝脏的放射性活性最高。其次是肾脏、膀胱、食管和脾脏。肺和大脑中的放射性活性水平较低。在大鼠服用3H-FC后，血液中的放射性活性在三个小时达到高峰，但在24小时后，大约50%的放射性仍然存留在血液中。在大鼠体内，48小时内通过尿液排出的放射性总排泄量约为30.7%，而约27.8%出现在粪便中。只有5.4%的未改变的FC通过尿液排出，而FC的其他代谢物占总尿液放射性活性的94.6%。FC在大鼠食管组织中的DNA结合也发生了。

In this paper, the distribution and elimination of 3H-Fusarin C (3H-FC) in rats and DNA-binding of FC in cultured explants of rat esophagus are reported. The radioactivity distribution in tissues was altered dynamically, and the highest levels of radioactivity were found in the intestine, stomach and liver after giving 3H-FC into the stomachs of rats. Kidney, bladder, esophagus and spleen followed. The radioactivity levels in the lung and brain were low. Radioactivity in the blood reached a peak three hours after giving 3H-FC to rats, but about 50% of the radioactivity remained in the blood even after 24 h. The total urinary excretion of radioactivity in rats was found to be about 30.7% within 48 h, and about 27.8% was present in the feces. Only 5.4% unchanged FC was excreted in the urine, while other metabolites of FC accounted for 94.6% of total urinary radioactivity. DNA-binding of FC occurred in rat esophageal explants.

来源:Hazardous Substances Data Bank (HSDB)

代谢

真菌毒素Fusarin C通过大鼠肝脏微粒体单加氧酶的代谢激活，形成了一种水溶性的致突变代谢物。然而，在没有NADPH生成系统的情况下，将Fusarin C与微粒体制剂一起孵化，会导致形成Fusarin PM1，这是一种高度水溶性的化合物，与Fusarin C一样，需要代谢激活才能具有致突变性。使用与Fusarin C结构相关的真菌毒素Fusarins A和D作为底物进行的酶学研究，以及Fusarin PM1的结构研究指出，Fusarin PM1是通过羧酸酯酶的作用形成的，该酶将C-20甲基酯基水解为自由的羧酸。

The metabolic activation of fusarin C by a rat liver microsomal monooxygenase resulted in the formation of a water-soluble mutagenic metabolite. However, fusarin C incubated in the presence of a microsomal preparation, but in the absence of an NADPH-generating system, led to the formation of fusarin PM1, a highly water-soluble compound which, like fusarin C, requires metabolic activation to be mutagenic. Enzyme studies using as substrates fusarins A and D, compounds structurally related to fusarin C, together with structural studies of fusarin PM1 indicated that fusarin PM1 was formed by the action of carboxylesterase which hydrolyses the C-20 methyl ester group to a free carboxylic acid.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

评估：对于人类来说，证据不足以证明由镰刀菌产生的毒素具有致癌性。对于实验动物来说，有足够的证据表明含有大量伏马毒素的镰刀菌培养物具有致癌性。对于实验动物来说，对于伏马毒素C的致癌性证据有限。总体评估：由镰刀菌产生的毒素可能对人类具有致癌性（2B组）。/由镰刀菌产生的毒素/

Evaluation: There is inadequate evidence in humans for the carcinogenicity of toxins derived from Fusarium moniliforme. There is sufficient evidence in experimental animals for the carcinogenicity of cultures of Fusarium moniliforme that contain significant amounts of fumonisins. There is limited evidence in experimental animals for the carcinogenicity of fusarin C. Overall evaluation: Toxins derived from Fusarium moniliforme are possibly carcinogenic to humans (Group 2B). /Toxins derived from Fusarium moniliforme/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

Dermatotoxin - 皮肤烧伤。 Toxic Pneumonitis - 由于吸入金属烟雾或有毒气体和蒸气引起的肺部炎症。 IARC Carcinogen - 3类：根据国际癌症研究机构，这些化学品无法分类。

Dermatotoxin - Skin burns. Toxic Pneumonitis - Inflammation of the lungs induced by inhalation of metal fumes or toxic gases and vapors. IARC Carcinogen - Class 3: Chemicals are not classifiable by the International Agency for Research on Cancer.

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

毒理性

• 相互作用

谷胱甘肽（GSH）与由串珠镰刀菌产生的致突变代谢物玉米赤霉醇C在化学和酶学上都有相互作用。这种化学反应是依赖于pH的，其结果是形成了玉米赤霉醇A和一个缺乏2-吡咯烷酮基团的化合物，这表明C-13-C-14环氧基团发生了相互作用。玉米赤霉醇C与GSH的酶学相互作用似乎也发生在这个位点，因为缺乏环氧基团的玉米赤霉醇A和D不能作为GSH-S-转移酶的底物。GSH与玉米赤霉醇C的相互作用似乎是一个重要的失活步骤，这可以解释在大鼠中观察到的玉米赤霉醇C缺乏致癌性的现象。

Glutathione (GSH) interacts both chemically and enzymatically with fusarin C, a mutagenic metabolite produced by Fusarium moniliforme. The chemical reaction, which is pH-dependent, results in the formation of both fusarin A and a compound that lacks the 2-pyrrolidone moiety thereby suggesting an interaction at the C-13-C-14 epoxide. Enzymatic interaction of fusarin C with GSH also appears to occur at this site as fusarins A and D, which lack the epoxide, do not serve as substrates for GSH-S-transferases. The interaction of GSH with fusarin C appears to be an important deactivation step which could explain the lack of carcinogenicity observed for fusarin C in rats.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……监测休克，如有必要，进行治疗……预计可能出现癫痫，如有必要，进行治疗……对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用生理盐水连续冲洗每只眼睛……不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔并给予5毫升/千克，最多200毫升的水进行稀释……在去污后，用干的无菌敷料覆盖皮肤烧伤……/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。监测心率和必要时治疗心律失常... . 使用D5W开始静脉输液 /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿... . 对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象... . 使用地西泮（安定）治疗癫痫... . 使用丙美卡因氢氯化物协助眼部冲洗... . /毒药A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-Fusarin C 通过灌胃给予大鼠。放射性标记物在肠道、胃和肝脏中的含量最高；在肾脏、膀胱、食道和脾脏中的含量较低。肺和大脑中的放射性标记物水平很低。血液中的放射性标记物在给药后3小时达到峰值，但在24小时后仍然存在于血液中。在48小时内，总尿排泄的放射性标记物约占31%，约有28%通过粪便排出。仅有5.4%的未改变的Fusarin C通过尿液排出，代谢物占总尿放射性标记物的94.6%。

(3)H-Fusarin C /was/ given by gavage to rats. The highest levels of radiolabel were found in the intestines, stomach and liver; lower levels were found in the kidney, bladder, esophagus and spleen. Levels of radiolabel in the lungs and brain were low. Those in the blood reached a peak at 3 hours after administration, but remained in the blood even after 24 hours. Total urinary excretion of radiolabel was found to be about 31% within 48 hours, and about 28% was excreted in the feces. Only 5.4% unchanged fusarin C was excreted in the urine, and metabolites accounted for 94.6% of the total urinary radiolabel.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (2E,3E,5E,7E,9E)-2-亚乙基-11-[(1R,2S,5R)-2-羟基-2-(2-羟基乙基)-4-氧代-6-氧杂-3-氮杂双环[3.1.0]己烷-5-基]-4,6,10-三甲基-11-氧代十一碳-3,5,7,9-四烯酸甲酯 生成 (2E,3E,5E,7E,9E)-2-ethylidene-11-[(1R,4S,5R)-4-hydroxy-4-(2-hydroxyethyl)-2-oxo-6-oxa-3-azabicyclo[3.1.0]hexan-1-yl]-4,6,10-trimethyl-11-oxoundeca-3,5,7,9-tetraenoic acid
  参考文献：
  名称：

  LU, S. -J.;LI, M. H.;JEFFREY, A. M., J. LABELL. COMPOUNDS AND RADIOPHARM., 27,(1989) N, C. 939-943

  摘要：

  DOI：

文献信息

• Structure elucidation of fusarin C, a mutagen produced by Fusarium moniliforme
  作者：Wentzel C. A. Gelderblom、Walter F. O. Marasas、Pieter S. Steyn、Pieter G. Thiel、Kirsten J. van der Merwe、Petrus H. van Rooyen、Robert Vleggaar、Philippus L. Wessels

  DOI：10.1039/c39840000122

  日期：——

  The assignment of structure (1) to fusarin C, a mutagen isolated from cultures of Fusarium moniliforme is based on a detailed study of its high-field 1H and 13C n.m.r. spectra and X-ray crystallography of the 8Z isomer of (1) which defined the substitution pattern and relative configuration of the 2-pyrrolidone moiety; nuclear Overhauser enhancement experiments indicate that the 2E,4E,6E,8E,10E polyene

  结构（1）对镰刀菌C（一种从镰刀镰刀菌培养物中分离的诱变剂）的分配基于对它的高场1 H和13 C nmr光谱以及（1的8 Z异构体的X射线晶体学的详细研究），其定义了2-吡咯烷酮部分的取代模式和相对构型；核Overhauser增强实验表明（1）的2 E，4 E，6 E，8 E，10 E多烯发色团在溶液中以两个顺式构象异构体之间的平衡存在和C-5–C-6单键的反式拓扑。