Rubratoxin A | 22467-31-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Rubratoxin A
• 英文别名: 3,13-dihydroxy-2-(1-hydroxyheptyl)-10-[hydroxy-(6-oxo-2,3-dihydropyran-2-yl)methyl]-6,14-dioxatricyclo[10.3.0.04,8]pentadeca-1(12),4(8)-diene-5,7,15-trione
• CAS: 22467-31-8
• 化学式: C₂₆H₃₂O₁₁
• 分子量: 520.5
• InChiKey: XOEFANNJIKAWGX-UHFFFAOYSA-N

物化性质

• 熔点：
  210-214℃ (decomposition)
• 溶解度：
  乙腈：可溶；二甲基亚砜：可溶
• 颜色/状态：
  NEEDLES FROM ETHYL ACETATE
• 稳定性/保质期：

  STABLE AT ROOM TEMP /RUBRATOXINS/

• 旋光度：
  Specific optical rotation: +84 deg (acetone, 20 °C, c=2)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  177
• 氢给体数：
  4
• 氢受体数：
  11

ADMET

代谢

除了完成葡萄糖到二氧化碳和水的氧化过程外，三羧酸循环还提供了生物合成一些次级代谢物所需的中间体，包括鲁布拉毒素...第一步涉及癸酸与草酰乙酸的缩合，类似于柠檬酸的形成方式。随后的脱水、脱羧和氧化导致形成一个中间酐，该酐二聚后，在进一步氧化作用下，形成鲁布拉毒素A。氧气功能在哪个阶段引入尚不清楚，特别是，这样的假设将意味着α,β-不饱和γ-内酯的羧基来自乙酸的甲基碳。

AS WELL AS SERVING TO COMPLETE THE OXIDATION OF GLUCOSE TO CO2 & WATER, THE TRICARBOXYLIC ACID CYCLE ALSO PROVIDES INTERMEDIATES FOR THE BIOSYNTHESIS OF SOME SECONDARY METABOLITES, INCL THE RUBRATOXINS... THE FIRST STEP INVOLVES CONDENSATION OF DECANOIC ACID WITH OXALOACETIC ACID IN A MANNER ANALOGOUS TO THE FORMATION OF CITRIC ACID. SUBSEQUENT DEHYDRATION, DECARBOXYLATION & OXIDATION LEAD TO AN INTERMEDIATE ANHYDRIDE WHICH DIMERIZES TO FORM, AFTER FURTHER OXIDATION, RUBRATOXIN A. AT WHAT STAGE THE OXYGEN FUNCTIONS ARE INTRODUCED IS NOT CLEAR, &, IN PARTICULAR, SUCH A HYPOTHESIS WOULD MEAN THAT THE CARBOXYL GROUP OF THE ALPHA,BETA-UNSATURATED GAMMA-LACTONE WOULD BE DERIVED FROM THE METHYL CARBON OF ACETATE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

RUBRATOXIN A 作为次级代谢物与 RUBRATOXIN B（来自红青霉和紫色链霉菌的主要代谢物）一起出现。

RUBRATOXIN A OCCURS AS THE MINOR METABOLITE ALONG WITH RUBRATOXIN B, THE MAJOR METABOLITE FROM.../PENICILLIUM RUBRUM & P PURPUROGENUM/.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一个无菌的葡萄糖-矿物盐肉汤被接种了红霉素的孢子悬浮液或菌丝团，并在静止状态下培养了14天。通过醚提取培养滤液并经薄层色谱法解析得到红霉素毒素。加入丙二酸盐可以增强毒素形成，但加入乙基丙二酸盐、莽草酸、醋酸盐或异柠檬酸和草酸乙酰在丙二酸盐存在下时，对毒素形成的影响不大。当单独或与丙二酸盐联合添加柠檬酸盐、顺式乙酰水杨酸、α-酮戊二酸盐、琥珀酸盐、延胡索酸盐和丙二酸盐时，会导致红霉素毒素的形成减少15-50%。乙酰辅酶A（10-15摩尔/瓶）使毒素产量增加80%。在10-3摩尔浓度下，柠檬酸盐可以刺激红霉素A的产量高达100%。超过10-3摩尔，柠檬酸盐会抑制毒素产生。丙二酸盐和延胡索酸盐+丙二酸盐可以增强(2-14)C-醋酸盐掺入红霉素。丙酮酸盐+丙二酸盐使(2-14)C-醋酸盐掺入红霉素的增加了40%。琥珀酸盐或α-酮戊二酸盐与丙二酸盐联合使用，导致标记醋酸盐掺入的最大减少（36%）。

A STERILE GLUCOSE-MINERAL SALTS BROTH WAS INOCULATED WITH SPORE SUSPENSIONS OR MYCELIAL PELLETS OF PENICILLIUM RUBRUM AND INCUBATED QUIESCENTLY FOR 14 DAYS. RUBRATOXINS WERE RECOVERED FROM CULTURE FILTRATES BY ETHER EXTRACTION AND RESOLVED BY TLC. TOXIN FORMATION WAS ENHANCED BY MALONATE BUT WAS NOT MARKEDLY AFFECTED BY ETHYL MALONATE, SHIKIMATE, AND ACETATE OR BY ISOCITRATE OR OXALOACETATE ADDED IN THE PRESENCE OF MALONATE. CITRATE, CIS-ACONITATE, ALPHA-KETOGLUTARATE, SUCCINATE, FUMARATE AND MALONATE WHEN PRESENT IN THE MEDIUM ALONE OR IN CONJUNCTION WITH MALONATE CAUSED A 15-50% REDUCTION IN RUBRATOXIN FORMATION. ACETYL-COA (10-15 MOL/FLAS) CAUSED AN 80% INCREASE IN TOXIN YIELD. AT 10-3 MOLAR, CITRATE STIMULATED RUBRATOXIN A PRODUCTION BY AS MUCH AS 100%. ABOVE 10-3 MOLAR, CITRATE INHIBITED TOXIN PRODUCTION. INCORPORATION OF (2-14)C-ACETATE INTO RUBRATOXIN WAS ENHANCED BY MALONATE AND FUMARATE + MALONATE. PYRUVATE + MALONATE PRODUCED A 40% INCREASE IN (2-14)C-ACETATE INCORPORATION INTO RUBRATOXIN. THE HIGHEST REDUCTION OF LABELED ACETATE INCORPORATION (36%) WAS CAUSED BY SUCCINATE OR ALPHA-KETOGLUTARATE COMBINED WITH MALONATE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏代谢丽红毒素。存在多种代谢物。在大鼠中，葡萄糖醛酸和硫酸结合物被排入胆汁，显然在小肠中被水解，并且母体毒素可能会通过肠肝循环再次被吸收。也会形成未知的代谢物。/丽红毒素/

THE LIVER METABOLIZES RUBRATOXINS. THERE ARE A NUMBER OF METABOLITES. IN RATS, GLUCURONIDE & SULFATE CONJUGATES ARE EXCRETED IN BILE, APPARENTLY HYDROLYZED IN THE INTESTINE, & THE PARENT TOXIN MAY BE RESORBED IN AN ENTEROHEPATIC CYCLE. UNKNOWN METABOLITES ARE ALSO FORMED. /RUBRATOXINS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

如bratoxin A 是一种强大的蛋白磷酸酶2A抑制剂，具有抗肿瘤和抗转移作用。其抑制作用可能通过磷酸化CREB并随后通过刺激T细胞释放白细胞介素-2来激活自然杀伤细胞，从而有助于抗转移效果。干扰细胞粘附的粘着斑激酶磷酸化和桩蛋白磷酸化可能是另一种抗转移效果。如bratoxin A 还被证明可以抑制Na+/K+-转运ATP酶。(A2987, A2988)

Rubratoxin A is a potent inhibitor of protein phosphatase 2A, exerting antitumor and antimetastatic effects. Inhibition may cause the phosphorylation of CREB and subsequent activation of natural killer cells via the stimulation of interleukin-2 release from T cells, contributing to antimetastatic effects. Focal adhesion kinase phosphorylation and paxillin phosphorylation that interfere with cell adhesion could be another antimetastatic effect. Rubratoxin A has also been shown to inhibit Na+/K+-transporting ATPases. (A2987, A2988)

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

Rubratoxins对肝脏有毒、对肾脏有毒、对脾脏有毒，会导致充血性、出血性和退行性病变。

Rubratoxins are hepatotoxic, nephrotoxic, and splenotoxic, causing congestive, hemorrhagic and degenerative lesions. (A2985, A2986)

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

• 副作用

职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

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