葫芦素 | 2222-07-3

• 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 - 类固醇和类固醇衍生物
• 中文名称: 葫芦素
• 中文别名: 葫芦素I；葫芦素 I
• 英文名称: cucurbitacin I
• 英文别名: [(9β,10α,16α,23E)-2,16,20,25-tetrahydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione]；cucurbitacin E；cucurbitacin-I；JSI 124；elatericin B；JSI-124；(8S,9R,10R,13R,14S,16R,17R)-17-[(E,2R)-2,6-dihydroxy-6-methyl-3-oxohept-4-en-2-yl]-2,16-dihydroxy-4,4,9,13,14-pentamethyl-8,10,12,15,16,17-hexahydro-7H-cyclopenta[a]phenanthrene-3,11-dione
• CAS: 2222-07-3
• 化学式: C₃₀H₄₂O₇
• 分子量: 514.659
• InChiKey: NISPVUDLMHQFRQ-MKIKIEMVSA-N

物化性质

• 熔点：
  148-150°C
• 沸点：
  698.3±55.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO 中≥22.45 mg/mL；不溶于乙醇；超声检测水中≥51.2 mg/mL
• LogP：
  2.330 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  132
• 氢给体数：
  4
• 氢受体数：
  7

安全信息

• 危险品标志：
  T+
• 安全说明：
  S28,S36/37,S45
• 危险类别码：
  R28
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811
• RTECS号：
  RC6200000
• 危险标志：
  GHS06
• 危险性描述：
  H300
• 危险性防范说明：
  P264,P301 + P310

制备方法与用途

生物活性

Cucurbitacin I 是 JAK2/STAT3 的天然选择性抑制剂，并具有有效的抗肿瘤活性。

靶点

• JAK2
• STAT3

体外研究显示，将 COLO205 细胞暴露于 Cucurbitacin I 后显著降低了细胞活力。Cucurbitacin I 抗癌作用的实现是通过下调 p-STAT3 和 MMP-9 表达完成的。预先处理心肌细胞后，PE 引起的细胞增大和 ANF 及 β-MHC 的上调被显著抑制。值得注意的是，Cucurbitacin I 也抑制了成纤维细胞生长因子 (CTGF) 和 MAPK 信号传导、促肥大因子以及 TGF-β/Smad 信号传导等导致纤维化的关键因素。将 Jak/Stat3 抑制剂 Cucurbitacin I 与 Seax 细胞共同培养后，P-Stat3 和 Stat3 的表达在时间和浓度上均呈依赖性下降。在新鲜分离的 Sz 细胞（n=3）中，Cucurbitacin I 导致 Stat3 表达浓度依赖性地下降，而 P-Stat3 无法检测到。最后，在新鲜分离的 Sz 细胞（n=4）中，用 30 μM Cucurbitacin I 培养 6 小时后，大多数肿瘤细胞（73-91%）发生凋亡。

体内研究

在整个研究过程中未观察到主要副作用。结果显示，实验结束时的平均肿瘤体积如下：对照组，616 mm³ (±130)；CQ 组，580 mm³ (±107)；Cucurbitacin I 组，346 mm³ (±79)；联合治疗组，220 mm³ (±62)。与对照组、联合治疗组及 Cucurbitacin I 组之间的肿瘤体积差异具有统计学意义。此外，联合治疗的肿瘤在实验结束时表现出显著较低的平均肿瘤重量。同时，未观察到小鼠体重变化。

反应信息

• 作为反应物：
  描述：

  葫芦素 在 吡啶 、 氨 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 6.5h， 生成 C₃₄H₅₁NO₇
  参考文献：
  名称：

  葫芦素衍生物及其制备方法

  摘要：

  本发明公开了葫芦素B和葫芦素E的多种新衍生物，以及它们的盐，还公开了这些新衍生物的制备方法，这些新衍生物以及它们的盐，由于分别与葫芦素B、葫芦素E具有共同的基本结构，所以性质也基本与葫芦素B、葫芦素E一样，具有较好的抗癌、抗病毒、抗炎症和保肝脏作用，而且毒副作用较低。

  公开号：

  CN107857789B
• 作为产物：
  描述：

  葫芦素 D 在 溴苯 、 N,N-二甲基乙酰胺 、 sodium acetate 、 palladium diacetate 作用下， 反应 24.0h， 以38%的产率得到葫芦素
  参考文献：
  名称：

  Cucurbitacin D Is a Disruptor of the HSP90 Chaperone Machinery

  摘要：

  Heat shock protein 90 (Hsp90) facilitates the maturation of many newly synthesized and unfolded proteins (clients) via the Hsp90 chaperone cycle, in which Hsp90 forms a heteroprotein complex and relies upon cochaperones, immunophilins, etc., for assistance in client folding. Hsp90 inhibition has emerged as a strategy for anticancer therapies due to the involvement of clients in many oncogenic pathways. Inhibition of chaperone function results in client ubiquitinylation and degradation via the proteasome, ultimately leading to tumor digression. Small molecule inhibitors perturb ATPase activity at the N-terminus and include derivatives of the natural product geldanamycin. However, N-terminal inhibition also leads to induction of the pro-survival heat shock response (HSR), in which displacement of the Hsp90-bound transcription factor, heat shock factor-1, translocates to the nucleus and induces transcription of heat shock proteins, including Hsp90. An alternative strategy for Hsp90 inhibition is disruption of the Hsp90 heteroprotein complex. Disruption of the Hsp90 heteroprotein complex is an effective strategy to prevent client maturation without induction of the HSR. Cucurbitacin D, isolated from Cucurbita texana, and 3-epi-isocucurbitacin D prevented client maturation without induction of the HSR. Cucurbitacin D also disrupted interactions between Hsp90 and two cochaperones, Cdc37 and p23.

  DOI：

  10.1021/acs.jnatprod.5b00054

文献信息

• CUCURBITACIN COMPOUNDS
  申请人：Halaweish T. Fathi

  公开号：US20070099852A1

  公开（公告）日：2007-05-03

  Cucurbitacins, cucurbitacin derivatives, and methods for making and using the same are provided.

  提供了西葫芦苷、西葫芦苷衍生物的方法以及制备和使用它们的方法。
• Th-17 differentiation markers for rosacea and uses thereof
  申请人：Steinhoff Martin

  公开号：US10370714B2

  公开（公告）日：2019-08-06

  A method is described that uses ROR gamma t, or ROR alpha to diagnose rosacea and/or to screen inhibitors of Th17 differentiation, notably in inhibiting ROR gamma t or ROR alpha. Also described is a method of using these screened inhibitors in rosacea treatment.

  描述了一种利用 ROR gamma t 或 ROR alpha 诊断酒渣鼻和/或筛选 Th17 分化抑制剂的方法，特别是抑制 ROR gamma t 或 ROR alpha 的方法。还描述了将这些筛选出的抑制剂用于酒糟鼻治疗的方法。
• Chemosensory receptor ligand-based therapies
  申请人：Anji Pharma (US) LLC

  公开号：US10610500B2

  公开（公告）日：2020-04-07

  Provided herein are methods for treating conditions associated with a chemosensory receptor, including diabetes, obesity, and other metabolic diseases, disorders or conditions by administrating a composition comprising a chemosensory receptor ligand, such as a bitter receptor ligand. Also provided herein are chemosensory receptor ligand compositions, including bitter receptor ligand compositions, and methods for the preparation thereof for use in the methods of the present invention. Also provided herein are compositions comprising metformin and salts thereof and methods of use.

  本文提供了通过施用包含化感受体配体（如苦味受体配体）的组合物来治疗与化感受体相关的病症（包括糖尿病、肥胖症和其他代谢性疾病、失调或病症）的方法。本文还提供了化学感觉受体配体组合物，包括苦味受体配体组合物，及其用于本发明方法的制备方法。本文还提供了包含二甲双胍及其盐类的组合物和使用方法。
• Th17 differentiation markers for acne and uses thereof
  申请人：GALDERMA RESEARCH & DEVELOPMENT

  公开号：US10760129B2

  公开（公告）日：2020-09-01

  A method is described for using ROR gamma t or ROR alpha to diagnose acne and/or to screen inhibitors of Th17 differentiation. Specifically described, are methods of inhibiting ROR gamma t or ROR alpha and use of the screened inhibitors in acne treatment.

  描述了一种使用 ROR gamma t 或 ROR alpha 诊断痤疮和/或筛选 Th17 分化抑制剂的方法。具体描述了抑制 ROR gamma t 或 ROR alpha 的方法，以及将筛选出的抑制剂用于痤疮治疗的方法。
• Cucurbitacin E as a new inhibitor of cofilin phosphorylation in human leukemia U937 cells
  作者：Souichi Nakashima、Hisashi Matsuda、Ai Kurume、Yoshimi Oda、Seikou Nakamura、Masayuki Yamashita、Masayuki Yoshikawa

  DOI：10.1016/j.bmcl.2010.02.062

  日期：2010.5

  Cucurbitane-type triterpenes, cucurbitacins B and E, were reported to exhibit cytotoxic effects in several cell lines mediated by JAK/STAT3 signaling. However, neither compound inhibited phosphorylation of STAT3 in human leukemia (U937) cells at low concentrations. We therefore synthesized a biotin-linked cucurbitacin E to isolate target proteins based on affinity for the molecule. As a result, cofilin, which regulates the depolymerization of actin, was isolated and suggested to be a target. Cucurbitacins E and I inhibited the phosphorylation of cofilin in a concentration-dependent manner, and their effective concentrations having the same range as the concentrations at which they had cytotoxic effects in U937 cells. In addition, the fibrous-/globular-actin ratio was decreased after treatment with cucurbitacin E in HT1080 cells. These findings suggested that the inhibition of cofilin's phosphorylation increased the severing activity of cofilin, and then the depolymerization of actin was enhanced after treatment with cucurbitacin E at lower concentrations. (C) 2010 Elsevier Ltd. All rights reserved.