4beta,9alpha,12beta,13alpha,20-五羟基惕各-1,6-二烯-3-酮 | 17673-25-5

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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: 4beta,9alpha,12beta,13alpha,20-五羟基惕各-1,6-二烯-3-酮
• 英文名称: phorbol
• 英文别名: 4β-phorbol；(1S,2S,6R,10S,11R,13S,14R,15R)-1,6,13,14-tetrahydroxy-8-(hydroxymethyl)-4,12,12,15-tetramethyltetracyclo[8.5.0.02,6.011,13]pentadeca-3,8-dien-5-one
• CAS: 17673-25-5
• 化学式: C₂₀H₂₈O₆
• mdl: MFCD00065450
• 分子量: 364.439
• InChiKey: QGVLYPPODPLXMB-UBTYZVCOSA-N

物化性质

• 熔点：
  162-163° and 233-234°; mp 249-250°
• 比旋光度：
  D24 +102° (water); D20 +118° (c = 0.4 in dioxane)
• 沸点：
  415.62°C (rough estimate)
• 密度：
  1.4
• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL；乙醇：微溶； PBS（pH 7.2）：1 mg/mL
• 物理描述：
  Phorbol is a white solid. (NTP, 1992)
• 颜色/状态：
  Anhydrous crystals; two forms of solvated crystals from ethyl acetate; solvated crystals from methanol or ethanol
• 蒸汽压力：
  1.1X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Phorbol is unstable to prolonged exposure to air, light and ambient temperatures.
• 旋光度：
  Specific optical rotation (water): +102 deg at 24 °C/D; +118 deg at 20 °C/D (c = 0.4 in dioxane)
• 分解：
  Decomposes at 250-251 °C (solvent free)
• 解离常数：
  pKa: 12.5 at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  26
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  118
• 氢给体数：
  5
• 氢受体数：
  6

ADMET

代谢

厌氧培养来自巴豆的佛波醇（1）与人类肠道细菌共生，产生了五种代谢物：异佛波醇（2），脱氧佛波醇（3），4beta,9alpha,20-三羟基-13,15-塞科-1,6,15-巴豆三烯-3,13-二酮（4），4beta,9alpha,20-三羟基-15,16,17-三诺-1,6-巴豆二烯-3,13-二酮（5）和4beta,9a,20-三羟基-14(13-->12)-阿贝奥-12alphaH-1,6-巴豆二烯-3,13-二酮（6）。所有这些代谢物（2-6）通过光谱方法进行了鉴定和表征，包括二维（2D）-核磁共振。来自人类肠道的九种确定菌株显示出将1转化为这些代谢物的能力。

Anaerobic incubation of phorbol (1) from Croton tiglium with human intestinal bacteria afforded five metabolites: isophorbol (2), deoxyphorbol (3), 4beta,9alpha,20-trihydroxy-13,15-seco-1,6,15-tigliatriene-3,13-dione (4), 4beta,9alpha,20-trihydroxy-15,16,17-trinor-1,6-tigliadiene-3,13-dione (5) and 4beta,9a,20-trihydroxy-14(13-->12)-abeo-12alphaH-1,6-tigliadiene-3,13-dione (6). All these metabolites (2-6) were identified and characterized by spectroscopic means, including two-dimensional (2D)-NMR. Nine defined strains from the human intestine showed an ability to transform 1 to these metabolites.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：佛波醇是一种粉末，用于生物化学和医学研究。人类暴露和毒性：佛波醇缺乏在佛波酯中发现的淋巴细胞激活诱导性质。与佛波酯不同，佛波醇缺乏促肿瘤活性，在抑制人类黑素瘤细胞生长和刺激分化功能方面要么无效要么引起反应不良。动物研究：佛波醇（20微克/毫升）无生物活性，对从小鼠大脑中提取的制剂的结合位点没有影响。佛波醇在器官培养中不刺激新生小鼠颅骨的骨前列腺素E2合成和骨吸收。佛波醇在Friend病毒转化的前红细胞C1 745细胞中未显示红细胞分化。因此，佛波醇是佛波酯的无活性类似物。

IDENTIFICATION AND USE: Phorbol is a powder. It is used in biochemical and medical research. HUMAN EXPOSURE AND TOXICITY: Phorbol lacked the lymphocyte-activating inducing properties found in phorbol esters. Unlike phorbol esters, phorbol lacks tumor-promoting activity and it was either inactive or elicited poor response in inhibition of growth and stimulation of differentiated functions in human melanoma cells. ANIMAL STUDIES: Phorbol (20 ug/mL) was devoid of biological activity and had no effect on binding sites in prepn from mouse brain. Phorbol did not stimulate prostaglandin E2 synthesis in bone and bone resorption in neonatal mouse calvaria in organ culture. Phorbol showed no erythroid differentiation in Friend virus-transformed proerythroid C1 745 cells. Thus phorbol is inactive analog of phorbol esters.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

"菠萝"这个词用来描述一类天然存在的化合物，可以被称为tigliane二萜类。菠萝酯是通常以其肿瘤促进作用而知名的四环二萜类化合物。菠萝酯模仿了二酰基甘油（DAG）的作用，后者是蛋白激酶C的激活剂，调控不同的信号转导途径和其他细胞代谢活动。菠萝酯的生物活性对结构非常特异。即使在非常低的浓度下，喂食含有菠萝酯的饮食的动物也会表现出毒理学表现。这种毒性限制了将含有菠萝酯的许多营养植物和农业副产品用作动物饲料的使用。此外，除了具有抗营养和毒性效应外，一些菠萝酯衍生物还以其抗菌和抗肿瘤活性而闻名。菠萝酯的杀软体动物和杀虫性质表明其作为有效的生物杀虫剂和杀虫剂的潜力。菠萝本身并不诱导肿瘤，但在接触致癌剂亚致癌剂量后会促进肿瘤生长。TPA和相关菠萝酯被报道为纤溶酶原激活剂合成的强效刺激剂。在生物测定中，TPA、菠萝-12,13-二癸酸酯（PDD）和TPA beta-氧化物（TPA的衍生物）与纤溶酶原激活剂诱导和肿瘤促进之间观察到了良好的相关性。菠萝不涉及与细胞DNA的共价结合，实际上它模仿了转化的效果，如改变膜形态、增加饱和密度、改变细胞表面岩藻糖肽和增加纤溶酶原激活剂和鸟氨酸脱羧酶的水平。（A15429）菠萝的各种酯具有重要的生物性质，其中最值得注意的是通过激活蛋白激酶C作为肿瘤促进剂的能力。它们模仿二酰基甘油，即两个羟基与脂肪酸反应形成酯的甘油衍生物。最常见的菠萝酯是12-O-十四烷酰基-13-乙酰基菠萝酯（TPA），也称为菠萝-12-肉豆蔻酸-13-乙酯（PMA），它被用作生物医学研究工具，用于致癌模型。TPA与离子霉素一起也可以用来刺激T细胞的激活、增殖和细胞因子的产生，并用于这些细胞因子胞内染色的方案。（维基百科）

The term 'phorbol' is used to describe the family of naturally occurring compounds that can be referred to as tigliane diterpenes. Phorbol esters are the tetracyclic diterpenoids generally known for their tumor promoting activity. The phorbol esters mimic the action of diacyl glycerol (DAG), activator of protein kinase C, which regulates different signal transduction pathways and other cellular metabolic activities. The biological activities of the phorbol esters are highly structure specific. The phorbol esters, even at very low concentrations, show toxicological manifestations in animals fed diets containing them. This toxicity limits the use of many nutritive plants and agricultural by-products containing phorbol esters to be used as animal feed. Besides, possessing antinutritional and toxic effects, few derivatives of the phorbol esters are also known for their antimicrobial and antitumor activities. The molluscicidal and insecticidal properties of phorbol esters indicate its potential to be used as an effective biopesticide and insecticide. The phorbols themselves do not induce tumors but promote tumor growth following exposure to a subcarcinogenic dose of a carcinogen. TPA and related phorbols were reported to be a potent stimulator for plasminogen activator synthesis. A good correlation was observed between plasminogen activator induction and tumor promotion with TPA, phorbol 12,13-didecanoate (PDD), and TPA beta-oxide (a derivative of TPA) in bioassays. The phorbol does not involve covalent binding to the cellular DNA, in fact it mimics the effects of transformation such as alteration in membrane morphology, increased saturation density, altered cell surface fucose glycopeptides, and increased the level of plasminogen activator and ornithine decarboxylase. (A15429) Various esters of phorbol have important biological properties, the most notable of which is the capacity to act as tumor promoters through activation of protein kinase C. They mimic diacylglycerols, glycerol derivatives in which two hydroxyl groups have reacted with fatty acids to form esters. The most common phorbol ester is 12-O-tetradecanoylphorbol-13-acetate (TPA), also called phorbol-12-myristate-13-acetate (PMA), which is used as a biomedical research tool in models of carcinogenesis. TPA, together with ionomycin, can also be used to stimulate T-cell activation, proliferation, and cytokine production, and is used in protocols for intracellular staining of these cytokines. (Wikipedia)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

未列在IARC（国际癌症研究机构）的名单上。

Not listed by IARC.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 相互作用

12-O-十四烷酰基佛波醇13-醋酸(I)和佛波醇(II)增加了由中国仓鼠V79细胞培养中经过N-甲基-N'-硝基-N-亚硝基胍和甲基氧化偶氮醇醋酸盐处理的抗乌本苷突变体的恢复率。在两种情况下，I比II在促进突变体恢复方面更有效。

12-O-tetradecanoylphorbol 13-acetate (I) & phorbol (II) incr the recovery of ouabain-resistant mutants in N-methyl-N'-nitro-N-nitrosoguanidine- and methylazoxyethanol acetate-treated V79 chinese hamster cell cultures. In both cases I was more effective than II in promoting the mutant recovery.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

关于皮肤肿瘤促进机制的研究。在雌性小鼠中，先用7,12-二甲基苯并[a]蒽（DMBA）引发后，同时给予佛波醇和12-O-十四烷酰佛波醇-13-醋酸盐对促进过程没有影响。

Studies on the mechanism of skin tumor promotion. Phorbol given simultaneously with 12-o-tetradecanoylphorbol 13-acetate after 7,12-dimethylbenz[a]anthracene (DMBA) initiation in female mice had no effect on promotion.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T+
• 危险类别码：
  R26/27/28
• 危险品运输编号：
  UN 2811 6
• WGK Germany：
  3
• RTECS号：
  GZ0600000
• 海关编码：
  29062990
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 安全说明：
  S26,S27,S28,S36/37/39,S45
• 危险性防范说明：
  P264,P280,P302+P352+P332+P313+P362+P364,P305+P351+P338+P337+P313
• 危险性描述：
  H315,H319

制备方法与用途

生物活性方面，菲波尔（Phorbol）是一种有毒的二萜类化合物，其酯类化合物展现出非常高的生物活性。

反应信息

• 作为反应物：
  描述：

  4beta,9alpha,12beta,13alpha,20-五羟基惕各-1,6-二烯-3-酮 在 吡啶 作用下， 生成 佛波醇12-十四酸酯13-乙酸酯
  参考文献：
  名称：

  克罗托诺尔斯的部分合成

  摘要：

  描述了在佛波醇的 α-二醇基团与乙酸和长链脂肪酸混合功能性佛波醇-(12,13)​​-二酯的部分合成。合成的六种佛波二酯与具有刺激性和促肿瘤作用的乙酰佛波酰化物 A 相同1- 一种4, 乙4和乙7从巴豆油中分离。异构佛波醇-(12,13)​​-二酯 A2和乙7以及ASA3和乙4是关于脂肪酸残基的位置异构体对。对于迄今为止从巴豆油中分离出来的所有 11 种佛波醇·(12,13)​​-二酯，A 基团的化合物在 C-13 处带有长链脂肪酸残基，在 C-13 处带有短链脂肪酸残基，这可以概括为-12。B组化合物显示这些脂肪酸残基的相反位置。A 型和 B 型的异构佛波二酯可以通过它们在薄层色谱中的 Rf 值、它们的 IR 和质谱以及它们的 20-[4'-硝基苯基偶氮苯甲酸-(4)]-酯的熔点来区分. 通过所描述的合成路线，具有确定化学结构的佛波醇-(12,13)​​-二酯现在很容易获得。

  DOI：

  10.1515/znb-1968-0422
• 作为产物：
  描述：

  [(1S,6S,8R,9R,10R,11R,13S,15S)-9-[tert-butyl(dimethyl)silyl]oxy-8,12,12,15-tetramethyl-4,14-dioxo-1,6-bis(trimethylsilyloxy)-13-tetracyclo[8.5.0.02,6.011,13]pentadec-2-enyl] acetate 在 3,5-二甲基吡唑 、 chromium(VI) oxide 、 4-二甲氨基吡啶 、 selenium(IV) oxide 、 sodium tetrahydroborate 、 copper(l) iodide 、 二(氰基苯)二氯化钯 、 双[Α,Α-双(三氟甲基)苯甲醇合]二苯硫 、 三苯胂 、 叠氮基三甲基硅烷 、 四丁基氟化铵 、 三乙酰氧基硼氢化钠 、 sodium cyanoborohydride 、 氟化氢吡啶 、 溶剂黄146 、 barium(II) hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 、 苯 为溶剂， 生成 4beta,9alpha,12beta,13alpha,20-五羟基惕各-1,6-二烯-3-酮
  参考文献：
  名称：

  (+)-佛波醇的十九步全合成

  摘要：

  佛波醇是蒂利亚烷二萜家族的旗舰成员，已为人所知 80 多年，并因其引人入胜的化学结构和佛波醇酯的药用潜力而引起了众多化学家和生物学家的关注。获得有用数量的佛波醇和相关类似物依赖于从天然来源和半合成中分离出来。尽管进行了 40 年的努力，但由于化学合成的复杂性和氧原子的不寻常位置，化学合成一直无法与这些策略竞争。纯合成的对映体纯佛波醇仍然难以捉摸，生物合成甚至没有导致这个萜烯家族中最简单的成员。最近，eudesmanes、germacrenes、紫杉烷类和原原单烯类都受益于受两相萜烯生物合成逻辑启发的策略，其中强大的 C-C 键构建和 C-H 键氧化齐头并进。在这里，我们实施了一种两相萜烯合成策略，只需 19 步即可从丰富的单萜 (+)-3-carene 中实现 (+)-佛波醇的对映特异性全合成。这种合成路线的目的不是取代分离或半合成作为产生天然产物本身的一种手段，而是能够获得含有独特​​氧

  DOI：

  10.1038/nature17153

文献信息

• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。
• Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
  申请人：Cai Xiong Sui

  公开号：US20060104998A1

  公开（公告）日：2006-05-18

  The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the Formula (I): wherein R 1 , R 3 -R 5 , A, D, Y and Z are defined herein. The present invention also relates to the discovery that compounds having Formula (I) are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

  本发明涉及被代替的4H-香豆素及其类似物，由式（I）表示：其中R1，R3-R5，A，D，Y和Z在此处定义。本发明还涉及发现具有式（I）的化合物是caspase的激活剂和凋亡诱导剂。因此，本发明的caspase激活剂和凋亡诱导剂可用于诱导在发生细胞不受控制生长和异常细胞扩散的各种临床状况中的细胞死亡。
• SUBSTITUTED INDOLES
  申请人：Gant Thomas G.

  公开号：US20090191183A1

  公开（公告）日：2009-07-30

  Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文揭示了Formula I的替代吲哚半胱氨酸白三烯受体调节剂，其制备方法，药物组合物以及使用方法。
• N-acylpyrrolidin-2-ylalkylbenzamidine derivatives as inhibitors of factor Xa
  申请人：——

  公开号：US20030092698A1

  公开（公告）日：2003-05-15

  This invention is directed to N-acylpyrrolidin-2-ylalkylbenzamidine derivatives which useful for inhibiting the activity of Factor Xa, by contacting said derivatives with a composition containing Factor Xa. The present invention is also directed to compositions containing said derivatives, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.

  这项发明涉及N-酰基吡咯啉-2-基烷基苯甲酰胺衍生物，用于通过将这些衍生物与含有凝血因子Xa的组合物接触来抑制凝血因子Xa的活性。本发明还涉及含有这些衍生物的组合物、它们的制备方法，以及它们的用途，例如用于抑制凝血酶的形成或用于治疗患有与生理上有害的凝血酶过量相关的疾病状态的患者。
• [EN] STABILIZATION OF BIOMOLECULES USING SUGAR POLYMERS<br/>[FR] STABILISATION DE BIOMOLÉCULES AU MOYEN DE POLYMÈRES DE GLUCIDES
  申请人：UNIV CALIFORNIA

  公开号：WO2013112897A1

  公开（公告）日：2013-08-01

  Compositions and methods for stabilizing biomolecules are disclosed. Specifically, the compositions include novel homopolymers or copolymers containing trehalose side chains conjugated to biomolecules. When such homopolymers or copolymers are placed in close proximity to biomolecules, such as proteins, the homopolymers or copolymers protect and/or stabilize the biomolecule. The compositions and methods may be suitable for use in various industries such as healthcare (pharmaceuticals), molecular biology, biofuels, paper, personal care, detergent, photographic, rubber, brewing, dairy and food processing industries.

  揭示了用于稳定生物分子的组合物和方法。具体来说，这些组合物包括含有与生物分子共轭的海藻糖侧链的新型同聚物或共聚物。当这种同聚物或共聚物与生物分子（如蛋白质）放置在紧密接触时，同聚物或共聚物可以保护和/或稳定生物分子。这些组合物和方法可能适用于各种行业，如医疗保健（制药）、分子生物学、生物燃料、纸张、个人护理、洗涤剂、摄影、橡胶、酿造、乳制品和食品加工行业。