软骨藻酸 | 14277-97-5

• 物质功能分类: 分析化学 - 标准品 - 标准物质
• 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
• 中文名称: 软骨藻酸
• 中文别名: 二甲乙二烯咯三酸；Domoicacid=Domoins辵re
• 英文名称: domoic acid
• 英文别名: (2S,3S,4S)-4-[(2Z,4E,6R)-6-carboxyhepta-2,4-dien-2-yl]-3-(carboxymethyl)pyrrolidine-2-carboxylic acid
• CAS: 14277-97-5
• 化学式: C₁₅H₂₁NO₆
• 分子量: 311.335
• InChiKey: VZFRNCSOCOPNDB-AOKDLOFSSA-N

物化性质

• 熔点：
  213-217℃
• 沸点：
  451.38°C (rough estimate)
• 密度：
  1.1800 (rough estimate)
• 溶解度：
  甲醇：0.6 mg/mL
• 颜色/状态：
  Colorless crystal needles
• 蒸汽压力：
  1.5X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  When heated to decomposition it emits toxic vapors of /nitrogen oxides/.
• 折光率：
  Index of refraction = 1.55 /Predicted/
• 解离常数：
  pKa1: 1.85 (carboxylic acid), pKa2: 4.47 (carboxylic acid), pKa3: 4.75 (carboxylic acid), pKa4: 10.60 (amino group) at 20 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  124
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

毒理性

• 毒性总结

识别和使用：软骨藻酸形成无色晶体针状。软骨藻酸是一种兴奋性氨基酸，含有谷氨酸的结构，与高活酸相似。海藻Chondria armata可能含有软骨藻酸，植物的提取物在日本被用作驱虫药，剂量为每人20毫克，没有不良反应。它的杀虫性质也很早就为人所知，因为苍蝇一落在海藻上就会很快死亡。人类暴露和毒性：遗忘性贝类中毒（ASP）发生在摄入含有软骨藻酸的软体动物或可能的鱼类后。迄今为止，仅在加拿大爱德华王子岛收获的双壳类软体动物在人类中引起过中毒。然而，软骨藻酸已在日本、地中海地区、北美和南美的东海岸以及北美的西海岸的藻类或甲藻中发现。摄入含有软骨藻酸的软体动物后几小时到一天内，会出现胃肠道症状。这些症状可能包括恶心、呕吐、腹痛、腹泻、出血性胃炎和厌食。神经症状可能在几小时后或长达三天后出现，这取决于1987年观察到的爆发情况。这些症状包括各种症状，因患者而异：严重头痛、失去平衡或眩晕、视力障碍、记忆丧失。在更严重的情况下（老年和肾功能不全是最主要的两个风险因素）：症状包括混乱、定向障碍、沉默达两周；自主神经系统功能障碍，持续几天到几周（心律失常、血压不稳定、打嗝、支气管分泌过多，可能需要气管插管）；不自主咀嚼、扮鬼脸、肌阵挛、惊厥；昏迷。在107例确诊病例中，有4人死亡。永久性后遗症包括记忆丧失和周围神经病。软骨藻酸在Caco-2细胞中诱导微核形成，显示出其具有致突变潜力。动物研究：该毒素作为谷氨酸激动剂，对脊椎动物中枢神经系统和其他富含谷氨酸受体的器官具有兴奋性毒性。对成年非人灵长类动物的实验研究表明，软骨藻酸是一种剂量依赖性的催吐剂，可产生与兴奋性毒性一致的临床和神经病理学变化。对处理过的啮齿动物的行为评估表明，过度活跃和刻板抓挠是毒性的第一个功能标记。中剂量治疗与记忆障碍和行为过度反应有关，这表明唤醒和/或情绪有所改变。在高剂量下，软骨藻酸处理导致明显的神经毒性，其特征是惊厥、癫痫持续状态和治疗动物的死亡。软骨藻酸的暴露途径很重要，影响效果的严重程度；腹膜内和静脉内治疗的经典中毒迹象明显低于口服暴露的剂量。虽然发育研究较少，但软骨藻酸容易穿过胎盘并进入胎儿大脑。软骨藻酸与先天性畸形无关，但与暴露后代在运动行为和认知上的持续变化有关。比较研究表明，与软骨藻酸相关的功能损失可能是持久的，对中枢神经系统的损伤可能是进行性的。软骨藻酸在鱼类Oreochromis niloticus中具有致突变性，显著增加了微核、核异常以及DNA链断裂的频率。生态毒性研究：在对大量野生海狮的研究中表明，空间记忆缺陷与自然接触DA相关的右背海马损伤程度有关，而且接触还会破坏海马-丘脑脑网络。因为海狮是依靠灵活导航的动态捕食者，受损的空间记忆可能影响其在野外的生存。监测加利福尼亚海狮（Zalophus californianus）的健康状况表明，这种物种的软骨藻酸中毒的症状学和流行病学的变化与有毒藻华的增加有关。存在两种不同的临床综合征：急性软骨藻酸中毒，以及与以前亚致死剂量的毒素暴露后慢性后果相关的癫痫。

IDENTIFICATION AND USE: Domoic acid forms colorless crystal needles. Domoic acid is an excitatory amino acid containing the structure of glutamic acid and resembling kainic acid. Seaweed Chondria armata may contain domoic acid and extracts of the plant have been used in Japan as an ascaricidal medication at a dose of 20 mg/person without adverse effects. Its insecticidal properties were also known since flies die soon after landing on the seaweeds. HUMAN EXPOSURE AND TOXICITY: Amnesic shellfish poisoning (ASP) occurs after ingestion of bivalve molluscs or possibly fish contaminated with domoic acid. Until now, only bivalve molluscs harvested in Prince Edward Island, Canada, have produced poisonings in humans. However, domoic acid has been found in algae or dinoflagellates in Japan, the Mediterranean region, the East Coast of North and South America, and the West Coast of North America. After a delay of a few hours to one-day post ingestion of molluscs contaminated with domoic acid, gastrointestinal symptoms appear. They may include nausea, vomiting, abdominal cramps, diarrhea, hemorrhagic gastritis and anorexia. The neurological symptoms may occur after a delay of a few hours or up to three days according to the outbreak observed in 1987. These consist of a wide variety of symptoms varied among patients: severe headaches, loss of balance or dizziness, vision disturbances, memory loss. In more severe cases (old age and renal insufficiency being the two main risk factors): symptoms included confusion, disorientation, mutism for up to two weeks; autonomic nervous system dysfunction for a few days to a few weeks (cardiac arrhythmias, unstable blood pressure, hiccoughs, bronchial hypersecretion which may require endo-tracheal intubation); involuntary chewing, grimacing, myoclonia, convulsions; coma. Death occurred in 4 of the 107 confirmed cases. Permanent sequelae included memory loss and peripheral polyneuropathy. Domoic acid has mutagenic potential as revealed in Caco-2 cells by induction of micronucleus formation. ANIMAL STUDIES: The toxin acts as a glutamate agonist and is excitotoxic in the vertebrate central nervous system and other glutamate receptor-rich organs. Experimental studies with adult nonhuman primates have established that domoic acid is a dose-dependent emetic that produces clinical and neuropathological changes consistent with excitotoxicity. Behavioral evaluations of treated rodents have shown that hyperactivity and stereotypical scratching are the first functional markers of toxicity. Mid-dose treatment is associated with memory impairment and behavioral hyperreactivity, suggesting changes in arousal and/or emotionality. At higher doses, domoic acid treatment results in frank neurotoxicity that is characterized by seizures, status epilepticus and death in treated animals. The route of domoic acid exposure is important and influences the severity of effects; intraperitoneal and intravenous treatments produce classic signs of poisoning at significantly lower doses than oral exposure. While developmental studies are few, domoic acid readily crosses the placenta and enters the fetal brain. Domoic acid is not associated with congenital dysmorphia but is linked to persistent changes in motor behavior and cognition in exposed offspring. Comparative research suggests that functional losses associated with domoic acid can be persistent and injuries to the CNS can be progressive. Domoic acid was genotoxic in a fish Oreochromis niloticus, producing significant increases in the frequencies of micronuclei, nuclear abnormalities as well as DNA strand breaks. ECOTOXICITY STUDIES: It was shown in a large sample of wild sea lions, that spatial memory deficits are predicted by the extent of right dorsal hippocampal lesions related to natural exposure to DA and that exposure also disrupts hippocampal-thalamic brain networks. Because sea lions are dynamic foragers that rely on flexible navigation, impaired spatial memory may affect survival in the wild. Monitoring California sea lion (Zalophus californianus) health indicated that changes in the symptomatology and epidemiology of domoic acid toxicosis in this species are associated with the increase in toxigenic blooms. Two separate clinical syndromes exist: acute domoic acid toxicosis, and a second neurological syndrome characterized by epilepsy associated with chronic consequences of previous sub-lethal exposure to the toxin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

神经毒素 - 其他中枢神经系统神经毒素

Neurotoxin - Other CNS neurotoxin

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

毒理性

• 相互作用

加利福尼亚海狮（CSLs；Zalophus californianus）的胎儿中毒与海藻毒素软骨酸暴露有关。这些海狮体内积累了包括农药和工业产品在内的持久性环境污染物，如多氯联苯（PCBs）和多溴联苯醚（PBDEs）。发育期暴露于农药滴滴涕（DDT）及其稳定代谢物1,1-双-(4-氯苯基)-2,2-二氯乙烯（p,p '-DDE）已被证明会增强斑马鱼中软骨酸诱导的癫痫发作；然而，其他共存的污染物的贡献尚不清楚。我们制定了一个污染物混合物，包括PCBs、PBDEs、六氯环己烷（HCH）和氯丹，其水平与胎儿海狮脂肪组织报告的水平相符，以确定共存的持久性污染物与p,p '-DDE对化学诱导的斑马鱼癫痫发作的影响，作为海狮的模型。在神经发育前，通过浴液暴露或胚胎卵黄囊微注射，将胚胎暴露于p,p '-DDE，存在或不存在定义的污染物混合物（6-30小时后受精）。在大脑成熟（受精后7天）后，鱼类暴露于化学致痫剂，戊四唑或软骨酸；随后使用相机和行为跟踪软件监测和分析由此产生的癫痫行为变化。暴露于污染物混合物的受试者的诱导癫痫行为与仅暴露于p,p '-DDE的受试者之间没有显著差异。这些研究表明，在没有共存的PCBs、HCH、氯丹和PBDEs的情况下，p,p '-DDE负责导致对软骨酸癫痫发作敏感性增加的协同活性。

Fetal poisoning of California sea lions (CSLs; Zalophus californianus) has been associated with exposure to the algal toxin domoic acid. These same sea lions accumulate a mixture of persistent environmental contaminants including pesticides and industrial products such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Developmental exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its stable metabolite 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p -DDE) has been shown to enhance domoic acid-induced seizures in zebrafish; however, the contribution of other co-occurring contaminants is unknown. We formulated a mixture of contaminants to include PCBs, PBDEs, hexachlorocyclohexane (HCH), and chlordane at levels matching those reported for fetal CSL blubber to determine the impact of co-occurring persistent contaminants with p,p -DDE on chemically induced seizures in zebrafish as a model for the CSLs. Embryos were exposed (6-30 hr postfertilization) to p,p -DDE in the presence or absence of a defined contaminant mixture prior to neurodevelopment via either bath exposure or embryo yolk sac microinjection. After brain maturation (7 days postfertilization), fish were exposed to a chemical convulsant, either pentylenetetrazole or domoic acid; resulting seizure behavior was then monitored and analyzed for changes, using cameras and behavioral tracking software. Induced seizure behavior did not differ significantly between subjects with embryonic exposure to a contaminant mixture and those exposed to p,p -DDE only. These studies demonstrate that p,p -DDE--in the absence of PCBs, HCH, chlordane, and PBDEs that co-occur in fetal sea lions--accounts for the synergistic activity that leads to greater sensitivity to domoic acid seizures.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

膝沟藻酸（DA），一种由伪沟藻属硅藻产生的兴奋性氨基酸，是一种谷氨酸类似物，可导致被称为遗忘性贝类中毒的神经病理状况。迄今为止，DA的肾脏影响尚未得到充分认识，尽管肾脏过滤是系统消除的主要途径，并且肾脏表达离子型谷氨酸受体。为了描述DA的肾脏影响，我们给成年Sv128/Black Swiss小鼠注射了神经毒剂量的DA或低于已知毒性限制的剂量。DA在肾脏中选择性累积并引起了显著的肾血管和肾小管损伤，表现为急性肾小管坏死、凋亡和肾小管细胞剥脱，以及以细胞损伤的特征性空泡化和线粒体肿胀。剂量>/= 0.1 mg/kg的DA提高了肾脏损伤生物标志物肾损伤分子-1和中性粒细胞凝胶酶相关脂钙蛋白的水平，剂量>/= 0.005 mg/kg诱导了早期反应基因c-fos和junb的表达。同时给予DA和广谱兴奋性氨基酸拮抗剂犬尿氨酸可以抑制c-fos、junb和中性粒细胞凝胶酶相关脂钙蛋白的诱导。这些发现表明肾脏可能对兴奋性毒素激动剂敏感，在检查谷氨酸受体激活时应考虑肾脏影响。此外，这些结果表明DA是一种强效的肾毒素，确定人体接触的安全水平时可能需要考虑潜在的肾毒性。

Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses >/= 0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses >/= 0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

... DA增强了在静息状态的心肌细胞中KCl诱导的细胞内钙浓度([Ca(2+)](i))的增加，并增大了在电刺激的心肌细胞中尼卡地平敏感的钙瞬变。

... DA potentiated the KCl-induced increase in [Ca(2+)](i) in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca(2+) transients in electrically stimulated cardiomyocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给药时，需要给小鼠和大鼠分别给予35至70毫克/千克体重的多莫酸才能产生毒性。这种降低的毒性符合胃肠道吸收不良的情况：小鼠和大鼠粪便中排出的多莫酸分别占给药量的102 +/- 17%和98 +/- 12%（平均值 +/- 标准误）。由于人类中毒发生在估计的1-5毫克/千克体重的多莫酸水平，易感个体对多莫酸的口服毒性似乎比啮齿类动物更为敏感。

When administered orally doses of between 35 and 70 mg domoic acid/kg body weight were required to produce toxicity in mice and rats. This reduced toxicity is consistent with a lack of absorption from the gastro-intestinal tract: fecal excretion accounted for 102 +/- 17% and 98 +/- 12% (mean +/- SE) of the domoic acid administered to mice and rats, respectively. Since human intoxication occurred at an estimated 1-5 mg domoic acid/kg body weight, susceptible individuals appear to be more sensitive than rodents to the oral toxicity of domoic acid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

鹅膏酸（DA）是一种强效的神经毒素，对海洋野生动物和人类健康都有影响，包括在啮齿动物模型中孕期前暴露的发展效应。然而，关于DA在母体-胎儿传输期间的胎儿单位内的毒物代谢动力学知之甚少。在妊娠第20天即临产前，研究了怀孕大鼠及其幼崽的DA组织分布和毒物代谢动力学。给怀孕的Sprague Dawley大鼠静脉注射1.0 mg DA/kg的剂量，并在24小时内间隔取样母体血浆、胎儿血浆、胎盘、羊水和胎儿大脑样本。使用WinNonLin软件分析确定毒物代谢动力学参数。母体血浆DA对数浓度-时间曲线符合双室药代动力学特征，消除的alpha和beta半衰期分别为26.9和297分钟。胎盘的最大浓度（C(max)）为752 ng/mL，终末半衰期为577分钟。母体-胎儿在血浆室之间的转移率为31%，胎儿血浆在60分钟时的最大浓度为86 ng/mL，终末半衰期为553分钟。羊水和胎儿大脑的总体平均值分别为27 +/- 12 ng/mL和8.12 ng/g，并且在24小时内没有显示出消除的迹象。胎儿对DA的较长期保留，特别是在羊水中，表明胎儿在妊娠期间可能持续重新暴露，即使在小的暴露剂量下也可能导致疾病状态。这对加州海狮（Zalophus californianus）具有启示意义，它们在DA产生水华数月后表现出类似癫痫的疾病。

Domoic acid (DA) is a potent neurotoxin that has both marine wildlife and human health impacts, including developmental effects during prenatal exposure in rodent models. However, little is known regarding DA toxicokinetics in the fetal unit during maternal-fetal transfer. Tissue distribution and toxicokinetics of DA were investigated in pregnant rats and their pups just prior to birth at gestational day 20. Pregnant Sprague Dawley rats were given an intravenous dose of 1.0 mg DA/kg and samples of maternal plasma, fetal plasma, placenta, amniotic fluid and fetal brain were taken at intervals over 24 hr. Toxicokinetic parameters were determined using WinNonLin software analysis. Maternal plasma DA log concentration-time curves fit a two compartment pharmacokinetic profile, with alpha and beta half-lives of elimination of 26.9 and 297 min, respectively. Placenta had a C(max) of 752 ng/mL and a terminal half-life of 577 min. Maternal-fetal transfer between the plasma compartments was 31% with a fetal plasma C(max) of 86 ng/mL at 60 min and terminal half-life of 553 min. Amniotic fluid and fetal brain had overall averages of 27 +/- 12 ng/mL and 8.12 ng/g, respectively, and did not show evidence of elimination over 24 hr. The longer fetal retention of DA, particularly in amniotic fluid, indicates that the fetus may be continually re-exposed during gestation, which could potentially lead to a disease state even at small exposure dose. This has implications for the California sea lions (Zalophus californianus), which exhibit an epilepsy-like disease that arises months after DA producing blooms.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在智利北部，已经在几种双壳类物种中检测到了软骨酸（DA）。在Mesodesma donacium中，这是当地渔民最重要的商业物种之一，关于净化、该毒素的解剖分布以及作为减轻ASP疫情后果的姑息措施的可能性，目前尚无信息。M. donacium中的DA净化速度非常快，可以通过双室模型来适当描述。第一室和第二室的估计速率分别为1.27 d(-1)和0.24 d(-1)，两个室之间的转移率为0.75。具有高净化速率可以保护这种物种在伪拟菱形藻水华期间长时间不受影响。考虑到这一点，贝类对消费者不安全的时间非常短，因此DA疫情在地方渔场可能造成的经济损失应该是适度的。关于解剖分布，至少在吸收阶段，毒素在软组织中均匀分布，总毒素负荷对应于消化腺（DG）、足部（FT）和其他身体部分（OBF）分别为27%，32%和41%。由于每个器官对毒素浓度的贡献是重量贡献和毒素负荷的函数，毒素分布模式显示出以下趋势：“所有其他身体部分”（OBF）>足部（FT）>消化腺（DG）。因此，DA浓度最高，贡献接近72%，对应于可食用组织（OBF + FT），而DG（不可食用组织）只贡献剩余的28%。因此，鉴于M. donacium中软骨酸的解剖分布，消除消化腺并不会实质性地降低最终产品的毒性，因此选择性内脏切除并不能提高它们的人类食用质量。

In northern Chile, domoic acid (DA) has been detected in several bivalve species. In Mesodesma donacium, one of the most important commercial species for local fishermen, no information is available on depuration, or on the anatomical distribution of this toxin and its potential use as a palliative measure to minimize the consequences of ASP outbreaks. Deputation of DA is very fast in M. donacium, and can be adequately described by means of a two-compartment model. The estimated rates for the first and second compartments were 1.27 d(-1) and 0.24 d(-1), respectively, with a transfer rate between compartments of 0.75. Having high depuration rates protects this species from being affected by Pseudo-nitzschia blooms for an extended period of time. Taking this into account, the time in which the bivalves are unsafe for consumers is very short, and therefore the economic losses that could result by the DA outbreaks in local fisheries should be moderate. In relation to anatomical distribution, at least during the uptake phase, the toxin was evenly distributed within the soft tissues, with a total toxin burden corresponding to 27%, 32% and 41% for Digestive Gland (DG), Foot (FT) and Other Body Fractions (OBF), respectively. Since the contribution of each organ to the toxin concentration is a function of both weight contribution and toxin burden, the pattern of toxin distribution showed the following trend: "all other body fractions" (OBF) > Foot (FT) > Digestive Gland (DG). Thus, the highest concentration of DA, with a contribution close to 72%, corresponds to the edible tissues (OBF + FT), while the DG (non-edible tissue) only contributes the remaining 28%. Consequently, in view of the anatomical distribution of domoic acid in M. donacium, the elimination of the digestive gland does not substantially reduce the toxicity of the final product and therefore selective evisceration would not improve their quality for human consumption.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠和小鼠中关于尿液和粪便排泄的研究表明，几乎100%的给药剂量在36小时内通过粪便排出。

Studies in rats and mice on urinary and fecal excretion have shown that almost 100% of the administered dose is eliminated in the stools within a delay of 36 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37
• 危险类别码：
  R20/21/22
• WGK Germany：
  3
• RTECS号：
  UX9665100

制备方法与用途

软骨藻酸

作用

软骨藻酸（分子式：C15H21NO6，分子量：311.3）是由水中藻类产生的生物毒素。其结构与红藻氨酸和谷氨酸相似，作为红藻氨酸受体的兴奋剂发挥作用。目前已知能够产生该毒素的硅藻类有Pseudonitzschia australis、P. pungens f. multiseries 和 P. pseudodelicatissima 等。检测水中P. australis 的含量及软骨藻酸浓度，当该藻类在水中的含量仅为 4.0×10³/L 时即可检出软骨藻酸。

毒性

软骨藻酸具有神经兴奋作用和神经毒性，能够引起记忆损害，并导致中毒的人或动物死亡。

制备方法

一种利用海洋硅藻共栖细菌发酵制备遗忘性贝毒软骨藻酸的方法如下：

1. 菌株活化： 将斜面菌种接种到摇瓶种子液培养基中，在 30-32℃下培养 12-15 小时，得到活化菌株种子液。
2. 种子液准备： 向种子培养液中通入蒸汽加热，121-123℃灭菌 25-35 分钟，冷却至 30-31℃。采用火种接种法将活化菌株种子液接种到种子培养液中，通气搅拌，通气量为 40-50 L/min，搅拌速率为 160-180 r/min，30-33℃下恒温培养 15-18 小时，得到种子液。
3. 发酵： 向发酵液中通入蒸汽加热，121-123℃灭菌 25-35 分钟，冷却至 30-31℃。将步骤 2) 得到的种子液接种到发酵液中，通气搅拌，通气量为 40-60 L/min，搅拌转速 140-160 r/min，30-33℃下恒温培养 48-52 小时，得到遗忘性贝毒软骨藻酸发酵液。
4. 提取： 将遗忘性贝毒软骨藻酸发酵液进行板框过滤得到菌体，加入甲醇溶液，静置 10-20 分钟后过滤，得到一次提取液和过滤菌体；将过滤菌体再次加入甲醇溶液中，重复上述步骤两次，合并三次提取液，旋蒸浓缩，得到遗忘性贝毒软骨藻酸粗提物。
5. 纯化： 将遗忘性贝毒软骨藻酸粗提物进行洗脱，收集组分并旋转蒸发去除溶剂，获得白色粉末。

生物活性

Domoic acid ((-)-Domoic acid; L-Domoic acid) 是一种兴奋性神经递质，从海洋植物 Nitzschia pungens 中分离出来。Domoic acid 通过激活海藻酸酯受体 (kainate receptor) 产生神经毒性作用。

反应信息

• 作为反应物：
  描述：

  软骨藻酸 在 platinum(IV) oxide 氢气 作用下， 以 水 为溶剂， 反应 1.0h， 以18.6 mg的产率得到(2S,3S,4S)-3-Carboxymethyl-4-((E)-5-carboxy-1-methyl-hex-1-enyl)-pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  Walter, John A.; Falk, Michael; Wright, Jeffrey L. C., Canadian Journal of Chemistry, 1994, vol. 72, # 2, p. 430 - 436

  摘要：

  DOI：
• 作为产物：
  描述：

  (2S,3S,4S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-(1-[1,3]dioxolan-2-yl-ethyl)-3-(2-hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 在 甲醇 、 氢氧化钾 、 重铬酸吡啶 、 正丁基锂 、 jones reagent 、 sodium tert-pentoxide 、 对甲苯磺酸 、 臭氧 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 苯 为溶剂， 反应 101.5h， 生成 软骨藻酸
  参考文献：
  名称：

  Total synthesis of (-)-domoic acid. A revision of the original structure

  摘要：

  DOI：

  10.1021/ja00376a048

文献信息

• [EN] 3-'4-HETEROCYCLYL -1,2,3,-TRIAZOL-1-YL!-N-ARYL-BENZAMIDES AS INHIBITORS OF THE CYTOKINES PRODUCTION FOR THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES<br/>[FR] 3-'4-HETEROCYCLYL -1,2,3,-TRIAZOL-1-YL-N-ARYL-BENZAMIDES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE CYTOKINES POUR LE TRAITEMENT DE MALADIES INFLAMMATOIRES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2005090333A1

  公开（公告）日：2005-09-29

  Disclosed compounds of formula (I), which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

  公开的化合物式(I)，可以抑制与炎症过程有关的细胞因子的产生，因此可用于治疗涉及炎症的疾病和病理状况，如慢性炎症性疾病。还公开了制备这些化合物的方法以及包含这些化合物的药物组合物。
• MONOMERS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
  申请人：Barany Francis

  公开号：US20140194383A1

  公开（公告）日：2014-07-10

  Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.

  本发明描述了在水中介质中与一个、两个、三个或更多其他单体接触时能够形成具有生物学用途的多聚体的单体。在一方面，这样的单体可能能够在水介质中（例如，体内）与另一个单体结合形成多聚体（例如，二聚体）。考虑的单体可能包括一个配体部分、一个连接元素和一个连接器元素，连接器元素连接配体部分和连接元素。在水介质中，这样的考虑单体可能通过每个连接元素相互连接，因此可能能够实质上同时调节一个或多个生物分子，例如，调节蛋白质上的两个或多个结合域，或者调节不同蛋白质上的结合域。
• Anti-Cytokine Heterocyclic Compounds
  申请人：Goldberg Daniel

  公开号：US20060276496A1

  公开（公告）日：2006-12-07

  Heterocyclic compounds and analogues thereof and their use as inhibitors of Mitogen-Activated Protein Kinase-Activated Protein kinase-2 (MAPKAP-k2), and also to a method for preventing or treating a disease or disorder that can be treated or prevented by modulating the activity of MAPKAP-K2 in a subject and to pharmaceutical compositions and kits that include these MAPKAP-K2 inhibitors.

  杂环化合物及其类似物以及它们作为丝裂原活化蛋白激酶-2（MAPKAP-k2）抑制剂的用途，以及用于预防或治疗可以通过调节受试者中MAPKAP-K2活性来治疗或预防的疾病或紊乱的方法，以及包括这些MAPKAP-K2抑制剂的药物组合物和试剂盒。
• Cytokine inhibitors
  申请人：Gao Amy Donghong

  公开号：US20060046986A1

  公开（公告）日：2006-03-02

  Disclosed are compounds of formula (I) which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

  披露了公式(I)的化合物，它们抑制参与炎症过程的细胞因子的产生，因此在治疗涉及炎症的疾病和病理状态，如慢性炎症疾病方面是有用的。还披露了制备这些化合物的方法以及包含这些化合物的药物组合物。
• COFERONS AND METHODS OF MAKING AND USING THEM
  申请人：Barany Francis

  公开号：US20120295874A1

  公开（公告）日：2012-11-22

  The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.

  本发明涉及一种用于制备治疗性化合物的单体。该单体包括一个或多个可与目标分子结合的药效团，其解离常数小于300微摩尔，以及与药效团连接的连接元素。所述连接元素的分子量小于500道尔顿，通过直接连接或通过连接器间接与药效团相连。