(2R)-3-[(2R,6R,8S,11R)-2-[(E,2R)-4-[(2S,2'R,4R,4aS,6S,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid | 78111-17-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2R)-3-[(2R,6R,8S,11R)-2-[(E,2R)-4-[(2S,2'R,4R,4aS,6S,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid
• CAS: 78111-17-8
• 化学式: C₄₄H₆₈O₁₃
• 分子量: 805.0
• InChiKey: QNDVLZJODHBUFM-WUXSEAQRSA-N

物化性质

• 熔点：
  164-166 °C
• 比旋光度：
  D20 +21° (c = 0.33 in CHCl3); D25 +25.4° (c = 0.24 in CHCl3)
• 沸点：
  672.95°C (rough estimate)
• 密度：
  1.0795 (rough estimate)
• 溶解度：
  二甲基亚砜：≥1 mg/mL
• 颜色/状态：
  Crystals from dichloromethane/hexane; crystals from benzene-CHCl3
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 旋光度：
  Specific optical rotation = +21 deg at 20 °C/D (c = 0.33 in CHCl3); +25.4 deg at 25 °C/D (c = 0.24 in CHCl3)
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  57
• 可旋转键数：
  10
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  183
• 氢给体数：
  5
• 氢受体数：
  13

ADMET

代谢

食用了被海洋生物毒素软海绵酸（OA）污染的海鲜可能导致腹泻性贝类中毒，症状包括恶心、呕吐和腹痛。大鼠和人类的肝脏细胞色素P450单加氧酶（CYP）都能代谢OA。然而，代谢后的OA对肝细胞的毒性尚不清楚。我们研究的目的是检测在加入大鼠和人类重组CYP酶的情况下，HepG2细胞暴露于OA时的细胞效应，以研究物种差异。结果应与CYP特异性代谢物模式相关联。通过使用LC-MS/MS技术，建立了在大鼠和人类重组CYP酶中孵育后OA的比较代谢物轮廓。结果表明，OA代谢为氧化代谢物与解毒作用相关，主要由人类CYP3A4和CYP3A5催化。与人类CYP3A酶相比，大鼠Cyp3a1的解毒作用较低，而Cyp3a2对OA的激活作用观察到，与OA的整体转化能力较弱相一致。相比之下，人类和大鼠CYP1A2似乎将OA激活为细胞毒性中间体。总之，肝脏中可能发生不同的OA代谢机制。在低剂量的OA情况下，人类肝脏可能很好地抵御细胞毒性OA，但对于大量食用贝类的消费者，不能排除潜在风险。

The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.

来源:Hazardous Substances Data Bank (HSDB)

代谢

四达酸通过与人重组细胞色素P450 3A4的孵化产生了四种代谢物。通过MS/MS实验以及使用每种代谢物94和133微克的1D和2D NMR方法，已经确定了四种代谢物中两种的结构。第三种代谢物的结构是通过氧化成已知结构的代谢物确定的。与四达酸一样，这些代谢物是蛋白磷酸酶PP2A的抑制剂。尽管其中一种代谢物确实含有一个可能形成活性位点半胱氨酸加合物的α,β不饱和羰基，但所有代谢物都是PP2A的可逆抑制剂。

Four metabolites of okadaic acid were generated by incubation with human recombinant cytochrome P450 3A4. The structures of two of the four metabolites have been determined by MS/MS experiments and 1D and 2D NMR methods using 94 and 133 ug of each metabolite. The structure of a third metabolite was determined by oxidation to a metabolite of known structure. Like okadaic acid, the metabolites are inhibitors of protein phosphatase PP2A. Although one of the metabolites does have an alpha,beta unsaturated carbonyl with the potential to form adducts with an active site cysteine, all of the metabolites are reversible inhibitors of PP2A.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

作者们建立了一个神经母细胞瘤（SH-SY5Y）细胞系，其中细胞骨架蛋白异常磷酸化，由于奥克迪酸（OA）显著抑制蛋白磷酸酶活性，导致微管破坏。褪黑素显著防止了由OA诱导的细胞存活率和线粒体代谢活性的下降。此外，由OA诱导的神经丝（NF-）H/M亚单位的过度磷酸化/积累以及微管的破坏，被褪黑素显著抑制。

/The authors/ generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA). OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by melatonin. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by melatonin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在大鼠清醒状态下，向海马内微量注射奥卡酸（一种强大的蛋白磷酸酶1和2A的抑制剂），在大约20分钟内引起强烈的脑电图和行为上的边缘型癫痫发作，这些发作可以通过系统性给予NMDA受体拮抗剂（+）-5-甲基-10,11-二氢-5H-二苯并-[a,d]环庚烯-5,10-亚胺马来酸盐以及向海马内注射1-(5-异喹啉磺酰基)-2-甲基哌嗪（一种蛋白激酶抑制剂）来抑制。

In awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

奥卡地酸（OA）是一种海洋毒素，也是一种肿瘤促进剂和凋亡诱导剂。它主要抑制蛋白磷酸酶、蛋白质合成并增强脂质过氧化。Caco-2细胞分别仅用OA（15 ng/mL）或镉（Cd）（0.625和5 μg/mL）处理24小时后，蛋白质合成受到抑制（分别降低了42 +/- 5%，18 +/- 13%，和90 +/- 4%），而丙二醛（MDA）的产生量分别为2,235 +/- 129，1,710 +/- 20，和11,496 +/- 1,624 pmol/mg蛋白质。此外，每种有毒物质都在DNA中诱导了碱基修饰；氧化碱基和甲基化dC的增加。OA和镉的组合更具细胞毒性，并引起了更多的DNA碱基修饰；m(5)dC/(m(5)dC + dC)的比例从3 +/- 0.15增加到9 +/- 0.15，而8-(OH)-dG/10(5)dG的比例也增加了（从36 +/- 2到76 +/- 6）。OA和Cd的组合也增加了MDA的水平（16,874 +/- 2,189 pmol/mg蛋白质）。目前的结果强烈表明，由这两种有毒物质诱导的氧化应激导致的DNA损伤可能通过表观遗传过程显著增加其致癌性。

Okadaic acid (OA) is a marine toxin, a tumor promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Caco-2 cells were treated exclusively by OA (15 ng/mL) or cadmium (Cd) (0.625 and 5 ug/mL) for 24 hr, protein synthesis was inhibited (by 42 +/- 5%, 18 +/- 13%, and 90 +/- 4% respectively) while /malondialdehyde/ (MDA) production was 2,235 +/- 129, 1710 +/- 20, and 11,496 +/-1,624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m(5)dC/(m(5)dC + dC) was increased from 3 +/- 0.15 to 9 +/- 0.15 and the ratio 8-(OH)-dG/10(5) dG also (from 36 +/- 2 to 76 +/- 6). The combination of OA and Cd also increased the level of MDA (1,6874 +/- 2,189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

25纳摩尔奥克达酸能促进B16黑素瘤的DNA断裂，增加细胞脱落以及色素沉着�