山楂酸 | 4373-41-5

• 物质功能分类: 天然产物 - 萜类
• 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: 山楂酸
• 中文别名: 2Α-羟基齐墩果酸；马斯里酸；(2alpha,3beta)-2,3-二羟基齐墩果-12-烯-28-酸；山楂叶提取物
• 英文名称: maslinic acid
• 英文别名: 2α,3β-dihydroxyolean-12-en-28-oic acid；crategolic acid；2α,3β-dihydroxy-12-oleanen-28-oic acid；2α-hydroxy-oleanolic acid；crataegolic acid；masilinic acid；(4aS,6aR,6aS,6bR,8aR,10R,11R,12aR,14bS)-10,11-dihydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid
• CAS: 4373-41-5
• 化学式: C₃₀H₄₈O₄
• 分子量: 472.709
• InChiKey: MDZKJHQSJHYOHJ-LLICELPBSA-N

物化性质

• 熔点：
  267～269℃
• 沸点：
  570.0±50.0 °C(Predicted)
• 密度：
  1.14±0.1 g/cm3(Predicted)
• 溶解度：
  丙酮：可溶1mg/mL，澄清，无色
• LogP：
  7.870 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Crystalline solid
• 蒸汽压力：
  2.3X10-15 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 4.81 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  34
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

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（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。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……。预防癫痫发作，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0.9%的生理盐水（NS）持续冲洗每只眼睛……。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，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). 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 0.9% saline (NS) 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 ... . /Poisons 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、严重肺水肿或严重呼吸困难的病人，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。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸林格氏液。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……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and 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 severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

橄榄及其衍生物是地中海饮食的重要组成部分，被认为具有抗癌作用...研究了由五环三萜组成的橄榄提取物对HT-29细胞增殖和凋亡的影响，主要成分为马斯林酸（73.25%）和齐墩果酸（25.75%）。研究剂量依赖性效应显示，马斯林酸的EC50值为73.96 +/- 3.19 uM/L，齐墩果酸的EC50值为26.56 +/- 2.55 uM/L，具有抗增殖活性，且不表现出坏死。通过显微镜观察细胞膜通透性的变化，以及检测DNA片段，证实了凋亡现象，在用含有150和55.5 uM/L马斯林酸和齐墩果酸的橄榄果实提取物处理24小时的HT-29细胞中，分别有40.9 +/- 3.9%和24.5 +/- 1.5%的细胞出现这些变化。在处理24小时后，caspase-3以剂量依赖性方式被激活。含有200 uM/L马斯林酸和74 uM/L齐墩果酸的提取物使caspase-3样活性增加了6倍，与对照组细胞相比。细胞凋亡是通过内在途径诱导的，这是通过在用含有150和55.5 uM/L马斯林酸和齐墩果酸的橄榄果实提取物处理的细胞线粒体中产生超氧阴离子来证明的...

/ALTERNATIVE and IN VITRO TESTS/ Olives and their derivatives represent an important component of the Mediterranean diet that has been considered to be protective against cancer... the effect on cell proliferation and apoptosis in HT-29 cells of an extract from the skin of olives composed of pentacyclic triterpenes with the main components maslinic acid (73.25%) and oleanolic acid (25.75%) was investigated. Studies of the dose-dependent effects showed antiproliferative activity at an EC50 value of 73.96 +/- 3.19 uM/L of maslinic acid and 26.56 +/- 2.55 uM/L of oleanolic acid without displaying necrosis. Apoptosis was confirmed by the microscopic observation of changes in membrane permeability in 40.9 +/- 3.9% and detection of DNA fragmentation in 24.5 +/- 1.5% of HT-29 cells incubated for 24 hr with olive fruit extract containing 150 and 55.5 uM/L of maslinic and oleanolic acids, respectively. Caspase-3 was activated in a dose-dependent manner after incubation for 24 hr. The extract containing 200 uM/L maslinic acid and 74 uM/L oleanolic acid increased caspase-3-like activity to 6-fold that of control cells. Programmed cell death was induced by the intrinsic pathway, as evidenced by the production of superoxide anions in the mitochondria of cells treated with olive fruit extracts containing 150 and 55.5 uM/L of maslinic and oleanolic acids, respectively...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/替代和体外测试/ 蛋白激酶C（PKC）与致癌作用有关，在癌症进展过程中表现出不同的表达谱。对饮食植物化学物质在癌症信号通路调控方面的研究一直在进行，以寻找有效的信号调节剂。本研究旨在评估马斯林酸对人类B淋巴母细胞（Raji细胞）中PKC表达的抑制作用，并确定表达的PKC同种型。使用PepTag assay进行非放射性检测PKC，以确定马斯林酸对PKC活性的影响。在Raji细胞中，使用20 nM PMA诱导6小时获得最高表达。将马斯林酸的抑制效果与四种PKC抑制剂（H-7, rottlerin, sphingosine, staurosporine）和两种三萜类化合物（齐墩果酸和熊果酸）进行比较。马斯林酸、司他鲁斯汀、H-7、鞘氨醇、rottlerin、熊果酸和齐墩果酸的IC50值分别为11.52、0.011、0.767、2.45、5.46、27.93和39.29 uM。通过西方印迹法在Raji细胞中鉴定出四种PKC同种型，分别为PKC beta I、beta II、delta和zeta。马斯林酸以浓度依赖性方式抑制PKC beta I、delta和zeta的表达。这些初步结果表明，马斯林酸在Raji细胞中对PKC活性具有潜在的抑制作用。马斯林酸可能是一种有潜力的抗癌化学预防剂，可能参与调节通过PKC受体激活的许多下游信号通路。

/ALTERNATIVE and IN VITRO TESTS/ Protein kinase C (PKC) has been implicated in carcinogenesis and displays variable expression profiles during cancer progression. Studies of dietary phytochemicals on cancer signaling pathway regulation have been conducted to search for potent signaling regulatory agents. The present study was designed to evaluate any suppressive effect of maslinic acid on PKC expression in human B-lymphoblastoid cells (Raji cells), and to identify the PKC isoforms expressed. Effects of maslinic acid on PKC activity were determined using a PepTag assay for non-radioactive detection of PKC. The highest expression in Raji cells was obtained at 20 nM PMA induced for 6 hours. Suppressive effects of maslinic acid were compared with those of four PKC inhibitors (H- 7, rottlerin, sphingosine, staurosporine) and two triterpenes (oleanolic acid and ursolic acid). The IC50 values achieved for maslinic acid, staurosporine, H-7, sphingosine, rottlerin, ursolic acid and oleanolic acid were 11.52, 0.011, 0.767, 2.45, 5.46, 27.93 and 39.29 uM, respectively. Four PKC isoforms, PKC beta I, beta II, delta, and zeta were identified in Raji cells via western blotting. Maslinic acid suppressed the expression of PKC beta I, delta, and zeta in a concentration-dependent manner. These preliminary results suggest promising suppressive effects of maslinic acid on PKC activity in Raji cells. Maslinic acid could be a potent cancer chemopreventive agent that may be involved in regulating many downstream signaling pathways that are activated through PKC receptors.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  2940000000

制备方法与用途

药理作用

山楂酸是一种五环三萜酸，主要存在于油橄榄等多种天然植物中，对人体安全。近年来的研究发现，它具有抗癌、抗氧化、抗艾滋病、抗菌和抗糖尿病等多种生物活性，引起了广泛的关注。

西班牙格拉纳达大学的科学家们揭示了山楂酸能够抑制丝氨酸蛋白酶的作用机制。而这种蛋白酶正是艾滋病病毒所利用的关键酶之一，用于将病毒从感染细胞中释放到外部环境，进一步扩散至全身。因此，山楂酸在抗肿瘤和抗艾滋病方面表现突出，可以显著降低艾滋病病毒体内扩散的概率达80%。

注意事项

本品应低温干燥保存，特殊产品需要在氮气环境下保存。若长时间保存不当，其含量可能会有所下降。

生物活性

MAslinic acid 可抑制 NF-κB p65 的 DNA 结合活性，并消除 IκB-α 磷酸化。

目标靶点

• NF-κB

体外研究

• MAslinic acid (MA) 抑制 LPS 引发的 NF-κB 转位至细胞核和 IκB-α 的磷酸化。它还被证实能够抑制骨髓单核细胞中的破骨细胞生成，并在胰腺癌细胞中抑制 TNF-α 诱导的 NF-κB 活性及其下游基因的表达。
• 为了确认橄榄果渣提取物 (OPEs) 在 RAW264.7 细胞中的抗炎作用是否归因于 MAslinic acid，进行了剂量依赖性实验。结果显示，10-20 μM 的 MAslinic acid 是有效的浓度，显著抑制了 TNF-α 的产生，并减少了 IL-1、IL-6 和 COX-2 mRNA 表达。
• 在 LPS 引发的 RAW 264.7 细胞中，MAslinic acid (10 和 20 μM) 显著抑制 NF-κB p65 的 DNA 结合活性，并显著减少 LPS 引起的 IκB-α 磷酸化。

体内研究

当小鼠以 200 mg/kg 的剂量给予 MAslinic acid (MA) 后，4 小时后发现其能明显缓解 λ-卡拉胶诱导的足部肿胀，并显著抑制了炎症反应，与对照组相比（0.91±0.51 mm 和 1.79±0.4 mm）。

化学性质

易溶于吡啶和氯仿甲醇混合溶剂，微溶于甲醇和乙酸乙酯。来源包括红枣、橄榄、山楂等植物。

用途

用于含量测定/鉴定/药理实验等。 药理药效：抗肿瘤、抗艾滋病病毒、抗炎、抗菌等多种作用。

反应信息

• 作为反应物：
  描述：

  山楂酸 在 溴 、 sodium acetate 作用下， 以 溶剂黄146 为溶剂， 反应 0.17h， 以72%的产率得到(2α,3β) 2,3-dihydroxy-12-bromo-olean-28-oic acid 28,13-lactone
  参考文献：
  名称：

  The chemical and biological potential of C ring modified triterpenoids

  摘要：

  A convenient and elegant route has been developed to separate the natural regioisomers triterpenoids ursolic acid (UA) and oleanolic acid (OA) as well as derivatives thereof. Eleven unknown derivatives of OA were designed, synthesized, and their cytotoxicity was investigated. Further sixteen compounds were prepared to correlate all compounds in a SAR study. It could be shown that C-ring modifications of OA and UA have only a moderate influence onto the cytotoxic activity of the compounds but a significant impact onto the ability to trigger apoptosis in ovarian cancer cells (cell line A2780). (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.11.025
• 作为产物：
  描述：

  2-硒吩亚磺酸,5-甲基- 在 palladium on activated charcoal sodium tetrahydroborate 、 氢气 作用下， 以 四氢呋喃 为溶剂， 生成 山楂酸
  参考文献：
  名称：

  五环三萜。第2部分：作为糖原磷酸化酶抑制剂的山楂酸衍生物的合成和生物学评估。

  摘要：

  描述了一系列山楂酸衍生物的合成，并评估了它们对兔肌肉糖原磷酸化酶的作用。在这一系列化合物中，15（IC（50）= 7 microM）是最有效的GPa抑制剂。讨论了山梨酸衍生物的SAR。

  DOI：

  10.1016/j.bmcl.2005.10.014

文献信息

• [EN] NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS<br/>[FR] NOUVEAUX AGENTS ANTIDIABÉTIQUES UTILES AVEC DES DÉRIVÉS DE BENZIMIDAZOLE CYCLIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010051176A1

  公开（公告）日：2010-05-06

  Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

  结构式（I）的新化合物是AMP-蛋白激酶的激活剂，可用于治疗、预防和抑制由AMPK激活的蛋白激酶介导的疾病。本发明的化合物对于治疗2型糖尿病、高血糖、代谢综合征、肥胖、高胆固醇血症和高血压是有用的。
• Extracts of Isochrysis sp.
  申请人：Herrmann Martina

  公开号：US20100080761A1

  公开（公告）日：2010-04-01

  The present invention relates to extracts of Isochrysis sp., preferably Tahitian Isochrysis, its cosmetic, dermatological and/or therapeutic uses and compositions and cosmetic, dermatological or therapeutic products comprising such an extract of Isochrysis sp., preferably Tahitian Isochrysis.

  本发明涉及Isochrysissp.的提取物，优选为塔希提Isochrysis，及其在化妆品、皮肤病学和/或治疗学上的用途以及包含该Isochrysissp.提取物的化妆品、皮肤病学或治疗学产品，优选为塔希提Isochrysis。
• Heterocycle-substituted 3-alkyl azetidine derivatives
  申请人：Baker K. Robert

  公开号：US20070123505A1

  公开（公告）日：2007-05-31

  Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

  结构式（I）的新化合物是大麻素-1（CB1）受体的拮抗剂和/或逆向激动剂，并且在治疗、预防和抑制由CB1受体介导的疾病方面具有用处。本发明的化合物在治疗精神病、记忆缺陷、认知障碍、阿尔茨海默病、偏头痛、神经病、神经炎症性疾病（包括多发性硬化症和吉兰-巴雷综合征）、病毒性脑炎、脑血管意外和头部创伤的炎症后遗症、焦虑症、压力、癫痫、帕金森病、运动障碍和精神分裂症中作为中枢作用药物具有用处。这些化合物还可用于治疗物质滥用障碍、肥胖或进食障碍的治疗，以及治疗哮喘、便秘、慢性肠道假性梗阻、肝硬化、非酒精性脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）。
• Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides
  作者：Andres Parra、Francisco Rivas、Pilar E. Lopez、Andres Garcia-Granados、Antonio Martinez、Fernando Albericio、Nieves Marquez、Eduardo Muñoz

  DOI：10.1016/j.bmc.2008.12.041

  日期：2009.2

  Maslinic acid (1) has been coupled at C-28 with several α- and ω-amino acids by using solution- and solid-phase synthetic procedures. Twelve derivatives (2–13) with a single amino acid residue were prepared in solution phase, whereas a dipeptide (14), a tripeptide (15), and a series of conjugate dipeptides (16–24) were synthesized in solid phase. The anti-HIV activity of these compounds was assessed

  通过使用溶液和固相合成方法，山酸（1）在C-28处与几种α-和ω-氨基酸偶联。十二衍生物（2 - 13）与单一的氨基酸残基在溶液相中制备，而二肽（14），三肽（15），和一系列共轭二肽（16 - 24）在固相合成。在携带荧光素酶基因作为报告基因的病毒克隆感染的MT-2细胞上评估了这些化合物的抗HIV活性。虽然在山梨酸中（1）同时具有细胞毒性和抗病毒活性，但只有衍生物13和24 具有抗HIV-1活性，因此代表了一类新型的抗HIV-1化合物。
• NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL AS ANTI-DIABETIC AGENTS
  申请人：BOOKSER BRETT C.

  公开号：US20100081643A1

  公开（公告）日：2010-04-01

  Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

  结构式（I）的新化合物是AMP-蛋白激酶的激活剂，并且在治疗、预防和抑制由AMPK激活的蛋白激酶介导的疾病方面非常有用。本发明的化合物在治疗2型糖尿病、高血糖、代谢综合征、肥胖、高胆固醇血症和高血压方面非常有用。