10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid | 76964-07-3

• 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
• 英文名称: 10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid
• 英文别名: 2,3,24-Trihydroxy-12-ursen-28-oic acid
• CAS: 76964-07-3
• 化学式: C₃₀H₄₈O₅
• 分子量: 488.708
• InChiKey: JXSVIVRDWWRQRT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  35
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  98
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

毒理性

• 相互作用

亚洲酸是一种存在于药用植物中的五环三萜类化合物。本研究调查了这种化合物对人类结肠腺癌细胞系HT-29的细胞毒性效应，以及它对抗癌药物伊立替康盐酸盐（CPT-11）的增效作用。亚洲酸在HT-29细胞中以剂量依赖性方式表现出细胞毒性。观察到剂量依赖性的DNA片段化、annexin阳性的凋亡细胞和caspase-3的激活。caspase-3抑制剂以浓度依赖性方式抑制了DNA梯状物的形成。Bcl-2和Bcl-XL蛋白因亚洲酸处理而减少。这些结果表明，亚洲酸通过caspase-3激活在HT-29细胞中诱导了凋亡。进一步检测了CPT-11和亚洲酸联合处理对HT-29细胞的细胞毒性效应。同时处理或依次先暴露于亚洲酸再暴露于CPT-11显示出加性效应。当细胞首先暴露于CPT-11然后再暴露于亚洲酸时，观察到协同作用。这些结果提示，亚洲酸可以作为提高结肠癌细胞对CPT-11治疗敏感性的药物，或者作为减少CPT-11不良反应的药物。

Asiatic acid is a pentacyclic triterpene contained in medicinal plants. The cytotoxic effect of this compound and its augmentative effect on the anticancer drug irinotecan hydrochloride (CPT-11) were investigated in the human colon adenocarcinoma cell line HT-29. Asiatic acid dose-dependently showed cytotoxicity in HT-29 cells. DNA fragmentation, annexin-positive apoptotic cells, and caspase-3 activation were observed in a dose-dependent manner. A caspase-3 inhibitor suppressed the DNA ladder formation in a concentration-dependent manner. Bcl-2 and Bcl-XL proteins were decreased by asiatic acid treatment. These results indicate that asiatic acid induced apoptosis in HT-29 cells via caspase-3 activation. Cytotoxic effects of combined treatment with CPT-11 and asiatic acid on HT-29 cells were further examined. Simultaneous treatment or sequential exposure first to asiatic acid and then to CPT-11 showed an additive effect. Synergism was observed when cells were first exposed to CPT-11 and then to asiatic acid. These results suggest that asiatic acid can be used as an agent for increasing sensitivity of colon cancer cells to treatment with CPT-11 or as an agent for reducing adverse effects of CPT-11.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

亚细酸是一种五环三萜类化合物，据报道能够诱导多种人类癌细胞的凋亡。在当前研究中，我们评估了亚细酸对7,12-二甲基苯[a]蒽(DMBA)引发的ICR小鼠经12-O-十四烷基佛波醇-13-醋酸(TPA)介导的皮肤肿瘤发生的抗促瘤作用。在每次应用TPA之前局部应用亚细酸，可以显著减少皮肤肿瘤的形成。我们还发现，预先应用亚细酸减轻了TPA诱导的[3H]胸腺嘧啶掺入，这是皮肤肿瘤促发的传统标志。此外，亚细酸抑制了TPA诱导的一氧化氮(NO)生成和诱导型一氧化氮合酶(iNOS)和环氧合酶-2(COX-2)的表达，这些在肿瘤生长尤其是促发阶段起着重要作用。另外，局部应用选择性iNOS抑制剂氨胍(AG)和另一种iNOS抑制剂N(G)-硝基-L-精氨酸甲酯(NAME)，在TPA处理前30分钟，显著抑制了TPA诱导的COX-2表达。这些结果表明，亚细酸可能通过抑制NO和COX-2信号来发挥抗肿瘤生成作用。

Asiatic acid, a pentacyclic triterpene, has been reported to induce apoptosis of various human cancer cells. In the present study, we assessed the anti-tumor promoting effect of asiatic acid against 12-O-tetradecanoylphorbol 13-acetate (TPA)-mediated skin tumorigenesis in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated ICR mice. Topical application of asiatic acid prior to each application of TPA resulted in a significant reduction in skin tumor formation. We also found that pre-application of asiatic acid alleviated TPA-induced [3H]thymidine incorporation, which is a conventional marker for skin tumor promotion. In addition, asiatic acid inhibited the TPA-induced generation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which are known to play important roles in tumor growth, especially in the promotion stage. In addition, topical application of aminoguanidine (AG), a selective iNOS inhibitor, and N(G)-nitro-L-arginine-methyl ester (NAME), another iNOS inhibitor, 30 min prior to TPA treatment significantly inhibited the TPA-induced COX-2 expression. These results suggest that asiatic acid may exert anti-tumorigenesis through inhibitory actions in NO and COX-2 signals.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

亚洲酸和科罗索酸是在生物膜抑制实验中被识别为生物膜抑制剂的两种天然产物。我们评估了这两种化合物在旋转磁盘反应器（RDRs）中与托布拉霉素和环丙沙星联合使用时对铜绿假单胞菌生物膜活性的影响。为了确定我们系统的稳健性，对这些生物膜对托布拉霉素和环丙沙星的抗生素敏感性进行了评估。在RDR中产生的生物膜细菌显示出对10微克/毫升环丙沙星具有显著的耐受性，从而模拟了在难治性细菌感染中观察到的耐受性。这些研究进一步表明，非粘液型的铜绿假单胞菌可以形成对临床相关浓度的环丙沙星有耐受性的生物膜。亚洲酸或科罗索酸均未减少铜绿假单胞菌生物膜的活细胞密度。然而，这两种化合物均增加了生物膜细菌对随后托布拉霉素治疗的敏感性，表明亚洲酸和科罗索酸是增强抗生素活性的化合物。环丙沙星与随后托布拉霉素治疗之间也观察到了类似的统计相互作用。

Asiatic acid and corosolic acid are two natural products identified as biofilm inhibitors in a biofilm inhibition assay. We evaluated the activities of these two compounds on Pseudomonas aeruginosa biofilms grown in rotating disk reactors (RDRs) in combination with tobramycin and ciprofloxacin. To determine the ruggedness of our systems, the antibiotic susceptibilities of these biofilms were assessed with tobramycin and ciprofloxacin. The biofilm bacteria produced in the RDR were shown to display remarkable tolerance to 10 mug/ml of ciprofloxacin, thus mimicking the tolerance observed in recalcitrant bacterial infections. These studies further demonstrate that a nonmucoid strain of P. aeruginosa can form a biofilm that tolerates ciprofloxacin at clinically relevant concentrations. Neither asiatic acid nor corosolic acid reduced the viable cell density of P. aeruginosa biofilms. However, both compounds increased the susceptibility of biofilm bacteria to subsequent treatment with tobramycin, suggesting asiatic acid and corosolic acid to be compounds that potentiate the activity of antibiotics. A similar statistical interaction was observed between ciprofloxacin and subsequent treatment with tobramycin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

三萜类化合物对D-半乳糖胺（D-GalN）或四氯化碳（CCl4）损伤的大鼠原代肝细胞的保护作用及机制被研究。通过两步胶原酶灌注法分离大鼠肝细胞，并在RPMI 1640培养基中培养。评价了亚麻酸（AA）和β-甘草酸（GA）对D-GalN（2 mmol/L）或CCl4（10 mmol/L）损伤的肝细胞的保护作用。通过光学显微镜观察细胞形态，用MTT法测量细胞活力，自动分析仪测定AST和LDH。荧光法用于测试活性氧（ROS）、一氧化氮终产物（NOx）和还原型谷胱甘肽（GSH），JC-1染色用于确定线粒体膜电位（DeltaPsim）。D-GalN损伤后，用AA和GA处理可降低培养基中的AST和LDH（P<0.05），此外，AA增强了肝细胞活力（P<0.05）。此外，AA和GA显著减少了ROS和NOx的产生，并改善了D-GalN诱导的DeltaPsim丢失。AA还抑制了由于D-GalN和CCl4处理导致的GSH减少。AA和GA都能保护肝细胞免受D-GalN和CCl4的损伤，这与减少细胞内ROS和NOx、逆转GSH的减少以及改善DeltaPsim丢失有关。

...The protective effects and mechanism of triterpenoids on primarily cultured rat hepatocytes injured by D-galactosamine (D-GalN) or carbon tetrachloride (CCl4) /were investigated/. Rat hepatocytes were isolated by two-step collagenase perfusion and cultured in RPMI 1640 medium. Protective effects of asiatic acid (AA) and beta-glycyrrhetinic acid (GA) were evaluated on hepatocytes injured by D-GalN (2 mmol/L) or CCl4 (10 mmol/L). Cell morphology was observed by light microscope, cell viability was measured by MTT assay, AST and LDH were determined by an automatic analyzer. Fluorescence assay was applied to test reactive oxygen species (ROS), nitric oxide end products (NOx) and reduced glutathione (GSH), and JC-1 staining was used to determine mitochondria membrane potential (DeltaPsim). AST and LDH in medium were decreased when treated with AA and GA after D-GalN injury (P<0.05), furthermore AA enhanced the hepatocyte viability (P<0.05). Moreover, AA and GA significantly reduced ROS and NOx generation, and ameliorated DeltaPsim lost induced by D-GalN. AA also inhibited GSH decrease due to D-GalN and CCl4 treatment. Both AA and GA could protect hepatocytes from D-GalN and CCl4 injuries, which is associated with reducing intracellular ROS and NOx, reversing GSH depression and ameliorating DeltaPsim lost.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

从茅苍术的根部提取物中分离出了一种新型香豆酰三萜酸，3-O-反式对香豆酰基阿奇酸（1），以及五种已知的三萜酸，熊果酸（2），23-羟基熊果酸（3），科罗索酸（4），亚细亚酸（5）和桦木酸（6）。化合物1的结构是通过解释光谱数据来阐明的，特别是通过广泛的1D和2D NMR研究。所有分离物（1-6）在体外对其胰腺脂肪酶（PL）的抑制活性进行了评估。在所有分离物中，新化合物1对PL的抑制活性最高，IC(50)为14.95微M，其次是熊果酸（2，IC(50) = 15.83微M）。其他四种三萜酸（3-6）也显示出显著的PL抑制活性，IC(50)值在20.42到76.45微M之间。

A new coumaroyl triterpene, 3-O-trans-p-coumaroyl actinidic acid (1), as well as five known triterpenes, ursolic acid (2), 23-hydroxyursolic acid (3), corosolic acid (4), asiatic acid (5) and betulinic acid (6) were isolated from an EtOAc-soluble extract of the roots of Actinidia arguta. The structure of compound 1 was elucidated from interpretation of the spectroscopic data, particularly by extensive 1D and 2D NMR studies. All the isolates (1-6) were evaluated in vitro for their inhibitory activities on pancreatic lipase (PL). Of the isolates, the new compound 1 possessed the highest inhibitory activity on PL, with an IC(50) of 14.95 microM, followed by ursolic acid (2, IC(50) = 15.83 microM). The other four triterpenes (3-6) also showed significant PL inhibitory activity, with IC(50) values ranging from 20.42 to 76.45 microM.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

使用新的高效液相色谱（HPLC）分析方法研究了单次口服剂量（30或60毫克）和连续7天治疗（每天两次，每次30或60毫克）后，积雪草总三萜酸部分中亚细酸在体内的药代动力学。十二名健康志愿者按照随机交叉设计接受了每种治疗，试验之间间隔3周。达到最高血浆浓度的时间不受剂量差异或治疗方案的影响。单次给药30毫克或60毫克后计算的最高血浆浓度和0至24小时浓度-时间曲线下面积（AUC0-24）的差异可以通过不同的剂量方案来解释。然而，经过30毫克和60毫克的长期治疗后，最高血浆浓度、AUC0-24和半衰期显著高于相应的单次给药观察到的值。这种现象可以通过亚细酸和积雪草苷之间的代谢相互作用来解释，后者在体内转化为亚细酸。

A new HPLC assay method was used to investigate the pharmacokinetics of asiatic acid after oral administration of the total triterpenic fraction of Centella asiatica in single doses (30 or 60 mg) and after a 7-day treatment (30 or 60 mg twice daily). Twelve healthy volunteers received each treatment following a randomized cross-over design with trials separated by a 3-week interval. The time of peak plasma concentration was not affected by dosage difference or by treatment scheme. Differences in peak plasma concentration and area under the concentration vs. time curve from 0 to 24 hr (AUC0-24) calculated after 30 or 60 mg administration (single dose) were accounted for by the different dose regimen. However, after chronic treatment with both 30 and 60 mg, peak plasma concentrations, AUC0-24 and half-life were significantly higher than those observed after the corresponding single dose administration. This phenomenon could be explained by a metabolic interaction between asiatic acid and asiaticoside, which is transformed into asiatic acid in vivo.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

亚洲酸的比较稳态生物利用度在12名健康男性和女性志愿者中进行研究，他们在口服大约等摩尔剂量的亚洲酸（12毫克）或亚洲酸的糖苷衍生物，亚洲苷（24毫克）后进行研究。亚洲酸和亚洲苷都是市场上销售的皮肤病产品Madecassol的成分。亚洲苷通过水解切割糖部分在体内转化为亚洲酸。在两种给药方案下，亚洲酸的稳态AUC0-12小时值相似（服用亚洲酸后为614 +/- 250 ng.hr/mL，服用亚洲苷后为606 +/- 316 ng.hr/mL），表明在约等摩尔剂量下，两种成分的亚洲酸生物利用度相当。由于亚洲酸被认为是Madecassol中最具治疗活性的成分，当前数据表明，亚洲苷的治疗效果可能通过转化为亚洲酸来介导。

The comparative steady-state bioavailability of asiatic acid was studied in 12 healthy male and female volunteers following oral administration of approximately equimolar doses of either asiatic acid (12 mg) or the glycoside derivative of asiatic acid, asiaticoside (24 mg). Both asiatic acid and asiaticoside are constituents of the marketed dermatological product Madecassol. Asiaticoside is converted in vivo to asiatic acid by hydrolytic cleavage of the sugar moiety. Steady-state AUC0-12hr values for asiatic acid on either regimen were similar (614 +/- 250 ng.hr/mL following asiatic acid compared to 606 +/- 316 ng.hr/mL following asiaticoside) indicating comparable bioavailability for asiatic acid with the two ingredients at approximately equimolar doses. Since asiatic acid is considered to be the most therapeutically active ingredient of Madecassol, the current data suggest that the therapeutic effects of asiaticoside may be mediated through conversion to asiatic acid.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• [EN] TARGETED DELIVERY AND PRODRUG DESIGNS FOR PLATINUM-ACRIDINE ANTI-CANCER COMPOUNDS AND METHODS THEREOF<br/>[FR] ADMINISTRATION CIBLÉE ET CONCEPTIONS DE PROMÉDICAMENTS POUR COMPOSÉS ANTICANCÉREUX À BASE DE PLATINE ET D'ACRIDINE ET MÉTHODES ASSOCIÉES
  申请人：WAKE FOREST SCHOOL OF MEDICINE

  公开号：WO2013033430A1

  公开（公告）日：2013-03-07

  Acridine containing cispiaiin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective eisp!aiin compounds to the nucleus in cancer ceils is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C i^aikylene-phenyl-NH-C(0)-R.15, folic acid, av03 iniegriii RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazol.es, oxazoies, erlotinib, and/or mixtures thereof; wherein R]§ is a peptide.

  含有环丙啶结构的吖啶类化合物已被披露，显示出比其他顺铂类化合物更有效地对抗癌症。使用一种或多种氨基酸、一种或多种糖、一种或多种聚合醚、C i^aikylene-phenyl-NH-C(0)-R.15、叶酸、av03整合RGD结合肽、他莫昔芬、恩多西芬、表皮生长因子受体、抗体结合物、激酶抑制剂、二唑类化合物、三唑类化合物、噁唑类化合物、厄洛替尼和/或它们的混合物将这些更有效的吖啶类化合物传递到癌细胞核中的方法被披露；其中R]§是一个肽。
• SUBSTITUTED IMIDAZOLECARBOXYLATE DERIVATIVES AND THE USE THEREOF
  申请人：CHENGDU MFS PHARMA. CO., LTD.

  公开号：US20200369621A1

  公开（公告）日：2020-11-26

  A compound is shown in formula (I). The derivatives of the compound include a stereoisomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a metabolite, a deuterated derivative. The compound is a structurally novel substituted imidazole formate derivative. Substituted imidazole formate derivatives are used in preparing a drug with sedative, hypnotic and/or anesthetic effects, as well as a drug that can control the state of epilepsy. The compound has a good inhibitory effect on the central nervous system, and provides a new option for clinical screening of and/or preparation of a drug with sedative, hypnotic and/or anesthetic effects and controlling the state of epilepsy.

  化合物在式（I）中显示。该化合物的衍生物包括立体异构体、药用可接受的盐、溶剂合物、前药、代谢物、氘代衍生物。该化合物是一种结构新颖的取代咪唑甲酸酯衍生物。取代咪唑甲酸酯衍生物用于制备具有镇静、催眠和/或麻醉作用的药物，以及可以控制癫痫状态的药物。该化合物对中枢神经系统具有良好的抑制作用，并为临床筛选和/或制备具有镇静、催眠和/或麻醉作用以及控制癫痫状态的药物提供了新选择。
• QUATERNARY AMMONIUM SALT COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：WEST CHINA HOSPITAL, SICHUAN UNIVERSITY

  公开号：US20210107872A1

  公开（公告）日：2021-04-15

  A compound is shown in formula I and can be in the form of a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug, or a metabolite. The compound takes effect rapidly and has a long-time local anesthetic effect following a single dose, with the sensory nerve blocking time being greater than the motor nerve blocking time, has both a long-acting local anesthetic effect and a selective local anesthetic effect, significantly reduces side effects of the compositions QX314 and QX314 and a quaternary ammonium salt compound with surfactant structural characteristics, and is safer. The compound of formula I of the present invention and a pharmaceutically acceptable salt thereof can be used for preparing drugs that have a long-time local anesthetic effect and a selective local anesthetic effect.

  化合物在公式I中显示，可以是药学上可接受的盐的形式，或立体异构体，或溶剂合物，或前药，或代谢物。该化合物作用迅速，单剂量后具有长时间的局部麻醉效果，感觉神经阻滞时间大于运动神经阻滞时间，既具有长效局部麻醉效果又具有选择性局部麻醉效果，显著减少了QX314和QX314组分以及具有表面活性剂结构特征的季铵盐化合物的副作用，并且更安全。本发明的公式I的化合物及其药学上可接受的盐可用于制备具有长效局部麻醉效果和选择性局部麻醉效果的药物。
• FORMULATIONS FOR THE DELIVERY OF ACTIVE AGENTS TO INSECTS, PLANTS, AND PLANT PATHOGENS
  申请人：Preceres Inc.

  公开号：US20170325457A1

  公开（公告）日：2017-11-16

  The present disclosure is directed to formulations comprising (1) at least one formulation transport agent, (2) at least one complexing agent, and (3) at least one active agent that modulates one or more traits of a target insect, plant, or plant pathogen. The present disclosure is also directed to methods of delivering such formulations to the target organism, as well as to formulation transport agents used to prepare such formulations.

  本公开涉及包含（1）至少一种制剂运输剂、（2）至少一种络合剂和（3）至少一种调节目标昆虫、植物或植物病原体的一个或多个特征的活性剂的配方。本公开还涉及将这种配方传递给目标生物体的方法，以及用于制备这种配方的制剂运输剂。
• Sun protection compositions comprising semi-crystalline polymers and hollow latex particles
  申请人：Candau Didier

  公开号：US20090041691A1

  公开（公告）日：2009-02-12

  Topically applicable cosmetic/dermatological UV protection compositions having enhanced SPF contain at least one organic UV screening agent and/or at least one inorganic screening agent, such compositions also containing at least the following constituents (A) and (B): A) a semi-crystalline polymer which is solid at ambient temperature and has a melting point of greater than or equal to 30° C., containing a) a polymeric backbone and b) at least one crystallizable organic side chain and/or one crystallizable organic block forming part of the backbone of this said polymer, said polymer having a number-average molecular mass Mn of greater than or equal to 1,000, and B) hollow latex particles having a particle size ranging from 150 to 380 nm, formulated into a topically applicable, physiologically acceptable medium therefor.

  具有增强SPF的适用于化妆品/皮肤科的防紫外线保护组合物至少包含一种有机紫外线过滤剂和/或至少一种无机过滤剂，此类组合物还至少包含以下成分（A）和（B）： A）半结晶聚合物，室温下为固体，熔点大于或等于30°C，包含a）聚合骨架和b）至少一种可结晶有机侧链和/或作为该聚合物骨架一部分的可结晶有机块，该聚合物具有大于或等于1,000的数均分子质量Mn，以及 B）中空乳胶颗粒，粒径范围为150至380纳米，配制成适用于局部使用的、生理上可接受的介质。