醉茄素 A | 5119-48-2

• 物质功能分类: 分析化学 - 分析试剂 - 离子色谱试剂
• 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: 醉茄素 A
• 中文别名: 醉茄素A；枯萎素A
• 英文名称: withaferin-A
• 英文别名: (4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione；WFA；(4β,5β,6β,22R)-5 ,6-epoxy-4,22,27-trihydroxy-1-oxoergosta-2,24-dien-26-oic acid δ-lactone；Withaferin A；(1S,2R,6S,7R,9R,11S,12S,15R,16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one
• CAS: 5119-48-2
• 化学式: C₂₈H₃₈O₆
• 分子量: 470.606
• InChiKey: DBRXOUCRJQVYJQ-CKNDUULBSA-N

物化性质

• 熔点：
  252-253℃
• 比旋光度：
  D28 +125° (c = 1.30 in CHCl3)
• 沸点：
  680.7±55.0 °C(Predicted)
• 密度：
  1.28
• 闪点：
  226℃
• 溶解度：
  可溶于 DMSO（高达 20 mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  96.4
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

毒理性

• 肝毒性

尽管被广泛使用，但印度人参普遍被认为是安全的，没有主要的不良反应。在临床试验中，没有报告在治疗期间出现血清酶升高的情况，也没有提到严重的不良事件或肝毒性。然而，最近有几例报告称，服用标明含有印度人参的商业草药产品的患者出现了临床上明显的肝损伤。肝损伤在开始服用印度人参后2到12周出现，表现为胆汁淤积或混合型损伤、黄疸和瘙痒。免疫过敏和自身免疫特征并不突出。黄疸往往持续时间较长，但最终没有死亡或慢性损伤而得到解决。由于商业草药制剂通常是草药和营养产品的混合物，可能会被错误标记并含有未知的草药和药物，因此并不总是清楚报告的病例是否由印度人参及其成分之一引起，还是由污染物引起。然而，在几份报告中，检测了患者正在服用的商业产品，发现其中含有印度人参而没有其他污染物。因此，可以认为由印度人参引起的临床上明显的肝损伤虽然罕见，但确实存在。

Despite widescale use, ashwagandha is considered generally safe and without major adverse effects. In clinical trials, there have been no reports of serum enzyme elevations occurring during therapy and no mention of serious adverse events or hepatotoxicity. Recently, however, several cases of clinically apparent liver injury have been reported in patients taking commercial herbal products that are labelled as containing ashwagandha. The liver injury presented 2 to 12 weeks after starting ashwagandha with a cholestatic or mixed pattern of injury, jaundice and pruritus. Immunoallergic and autoimmune features were not prominent. Jaundice tended to be protracted but ultimately resolved without fatalities or chronic injury. Because commercial herbal preparations are often mixtures of herbs and nutritional products and can be mislabeled and contain unknown herbs and medications, it is not always clear whether the reported cases were due to ashwagandha and one of its components or to a contaminant. In several reported cases, however, the commercial product being taken was tested and found to have ashwagandha without other contaminants. Thus, clinically apparent liver injury attributable to ashwagandha appears to occur, but is rare.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的使用总结：印度人参（Withania somnifera）的根和浆果含有生物碱、甾体内酯和皂苷。在阿育吠陀医学中，它被称为印度人参，有时被用作催乳剂。然而，没有科学有效的临床试验支持这种用途。催乳剂不应替代影响乳汁产量的可改变因素的评估和咨询。目前没有数据表明印度人参的任何成分会排入母乳中，或者在哺乳母亲或婴儿中的安全性或有效性。通常情况下，印度人参在成人中耐受性良好，偶尔会出现严重腹泻、皮肤灼热、镇静和皮肤变色以及过敏反应。糖尿病、高血压或对激素敏感的前列腺癌患者应谨慎使用。因为没有关于在哺乳期间使用印度人参的已发表经验，应避免使用，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：40名产后5天抱怨乳汁不足的妇女被给予了含有野生芦笋200毫克、印度人参（Withania somnifera）100毫克、葫芦巴50毫克、甘草50毫克和大蒜20毫克的复合草本补充剂，每天3次，每次2粒胶囊（Lactare，印度马德拉斯的Pharma Private Ltd.生产）。治疗第4天，没有婴儿需要补充喂养。在母亲治疗的第5天，为了确定婴儿摄入的乳汁量，每次喂养前后都对婴儿进行称重。在测试称重的当天，婴儿的乳汁摄入量平均为388毫升，液态和卡路里的摄入量被认为是充足的。由于缺乏随机化、盲法、安慰剂对照以及母乳喂养技术的母亲指导，这项研究不能被视为这些草药具有催乳效果的 有效证据。此外，婴儿每天只哺乳6到8次，这不足以最大化乳汁产量。

◉ Summary of Use during Lactation:Withania (Withania somnifera) roots and berries contain alkaloids, steroidal lactones, and saponins. It is called ashwagandha in ayurvedic medicine where it is sometimes used as a galactogogue. However, no scientifically valid clinical trials support this use. Galactogogues should never replace evaluation and counseling on modifiable factors that affect milk production. No data exist on the excretion of any components of Withania into breastmilk or on the safety and efficacy of Withania in nursing mothers or infants. In general, Withania is generally well tolerated in adults with occasional severe diarrhea, skin burning, sedation and discoloration and allergic skin reactions. It should be used cautiously by patients with diabetes, hypertension or men with hormone-sensitive prostate cancer. Because there is no published experience with Withania during breastfeeding, it should be avoided, especially while nursing a newborn or preterm infant. Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products. More detailed information about dietary supplements is available elsewhere on the LactMed Web site. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Forty women who complained of an insufficient milk supply at 5 days postpartum were given a combination herbal supplement as 2 capsules of Lactare (Pharma Private Ltd., Madras, India) 3 times daily. Each capsule contained wild asparagus 200 mg, ashwagandha (Withania somnifera) 100 mg, fenugreek 50 mg, licorice 50 mg, and garlic 20 mg. By day 4 of therapy, no infants required supplementary feeding. Infants were weighed before and after each feeding on day 5 of maternal therapy to determine the amount of milk ingested. On the day of the test weighing, infants' milk intake averaged 388 mL, and the fluid and caloric intake was considered adequate. This study cannot be considered as valid evidence of a galactogogue effect of these herbs because it lacks randomization, blinding, a placebo control, and maternal instruction in breastfeeding technique. Additionally, infants were breastfed only 6 to 8 times daily, which is insufficient to maximize milk supply.

来源:Drugs and Lactation Database (LactMed)

安全信息

• 危险品标志：
  T
• WGK Germany：
  3
• 海关编码：
  29322090

制备方法与用途

生物活性

Withaferin A (WA, WFA) 可通过一种对硫代烷基化敏感的氧化还原机制，阻止肿瘤坏死因子诱导的 IκB 激酶 β 的激活，从而有效抑制 NF-κB 的激活。它还与中间丝状体蛋白（vimentin）结合，并表现出抗肿瘤和抗血管生成活性。Withaferin A 是从 Withania somnifera 分离的一种甾体内酯。

靶点

Target	Value
NF-κB
vimentin

体外研究

Withaferin A 具有抗炎活性，并通过一种对硫代烷基化敏感的氧化还原机制，有效抑制肿瘤坏死因子诱导的 IκB 激酶 β 的激活。此外，它还表现出抗癌活性。Withaferin A 可靶向 IF 蛋白 vimentin，在 3 μM 浓度下使牛主动脉内皮细胞（BAECs）中的 vimentin 纤维聚集，并在 10 μM 浓度下诱导内皮细胞中 vimentin 的片段化。单独使用 Withaferin A (0.5, 1.5 μM) 或与顺铂 (CIS) 联合使用，均能剂量依赖性地减少 ALDH1 阳性癌症干细胞的致瘤潜能。

体内研究

Withaferin A (2 mg/kg, i.p.) 在小鼠中表现出通过 vimentin 抑制血管生成的强大活性。在小鼠肿瘤组织中，Withaferin A (2 mg/kg) 联合顺铂 (CIS) 调节 ALDH1 标记物的表达，并下调 securin 的表达。

反应信息

• 作为反应物：
  描述：

  醉茄素 A 在 吡啶 、 咪唑 、 chromium(VI) oxide 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 27.08h， 生成 4-去氢醉茄素 A
  参考文献：
  名称：

  通过掺入硅来扩大Withaferin A的化学空间，以提高其在人卵巢癌细胞上的临床潜力。

  摘要：

  卵巢癌是全球第七大最常被诊断出的癌症。在此，我们报道了withaferin A（WA）-甲硅烷基醚文库的开发，该文库首次报道了30种类似物。对人上皮性卵巢癌顺铂敏感和耐药细胞系的细胞毒性试验鉴定出八种类似物，它们显示出纳摩尔效价（IC50为1至32 nM），高于先导化合物和参考药物。这种细胞毒性效力还与在非肿瘤细胞系上的良好选择性指数相结合。两种有效类似物的细胞周期分析显示，细胞凋亡通过细胞凋亡而没有表明细胞周期停滞在G0 / G1期。构效关系与计算机吸收，分布，代谢，排泄研究表明，WA框架中C-4处的硅和羰基基团的结合增强了效能，选择性和药物相似性。这些发现揭示了类似物22、23和25是复发性卵巢癌患者中临床翻译的潜在候选者。

  DOI：

  10.1021/acs.jmedchem.9b00146
• 作为产物：
  描述：

  2,3-dihydro-3β-O-sulfate withaferin A 在 吡啶 、 potassium carbonate 作用下， 反应 1.0h， 以93%的产率得到醉茄素 A
  参考文献：
  名称：

  2,3-二氢withaferinA-3β- O-硫酸盐，是通过气生生长的Withania somnifera获得的withaferin A的新潜在前药

  摘要：

  药用植物Withania somnifera（L.）Dunal的根的制剂在印度的阿育吠陀医学传统中已被使用了数千年，作为缓解紧张和增强健康的一般补品，特别是在老年人中。在现代，人们已经证明，非洲醉茄具有抗血管生成和抗癌活性，这在很大程度上归因于甾体内酯，其中Aferin A是主要成分。但是，当使用航空技术进行培养时，发现该植物会产生一种新的天然产物2,3-二氢枯草菌素A-3β- O-硫酸盐（1），它是从气生组织中提取的甲醇提取物的主要成分。1显示出的特征生物活性包括抑制癌细胞的增殖/存活，破坏细胞骨架组织和诱导细胞热休克反应，这与枯草杆菌素A（2）相似。细胞培养中1的起效延迟和1的效力降低，以及先前的观察结果表明，withanolides中的2（3）-双键具有生物活性的要求，这表明在细胞培养基中1可能转化为2，这一点得到了证实。 HPLC分析。通过气培植物获得的1的丰富产量，良好的水溶性和

  DOI：

  10.1016/j.bmc.2008.10.091

文献信息

• [EN] NOVEL SESQUITERPENOID STAT3 INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS DE STAT3 SESQUITERPÉNOÏDES
  申请人：UNIV HAWAII

  公开号：WO2014205416A1

  公开（公告）日：2014-12-24

  The present disclosure provides a method of purifying pharmaceutical compositions consisting essentially of STAT3 inhibitors from a mixture of compounds, pharmaceutical compositions comprising STAT3 inhibitors used to inhibit STAT3 in tumor cells, and certain pharmaceutically acceptable salts thereof, and methods of use. The present disclosure features, in some embodiments, novel, potent and selective STAT3 inhibitors, including sesquiterpene lactone inhibitors.

  本公开提供了一种从化合物混合物中纯化主要由STAT3抑制剂组成的药物组合物的方法，所述药物组合物包括用于抑制肿瘤细胞中的STAT3的STAT3抑制剂，以及其某些药用可接受的盐，以及使用方法。本公开在某些实施例中具有新颖、强效和选择性的STAT3抑制剂，包括倍半萜内酯抑制剂。
• [EN] SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS<br/>[FR] COMPOSÉS SUBSTITUÉS DE PYRAZOLO[1,5-A]PYRIDINE EN TANT QU'INHIBITEURS DE LA KINASE RET
  申请人：ANDREWS STEVEN W

  公开号：WO2018071447A1

  公开（公告）日：2018-04-19

  Provided herein are compounds of the Formula I and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X1, X2, X3, X4, Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

  本文件提供了公式I的化合物以及立体异构体和药用可接受的盐或溶剂化物，其中A、B、X1、X2、X3、X4、环D和E具有说明书中给出的含义，它们是RET激酶的抑制剂，可用于治疗和预防可通过RET激酶抑制剂治疗的疾病，包括与RET相关疾病和失调。
• [EN] SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRAZOLO[1,5-A]PYRIDINE SUBSTITUÉS EN TANT QU'INHIBITEURS DE LA KINASE RET
  申请人：ANDREWS STEVEN W

  公开号：WO2018071454A1

  公开（公告）日：2018-04-19

  Provided herein are compounds of the Formula I: (I) or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

  本文提供了Formula I的化合物：(I)或其药用可接受的盐或溶剂，其中A、B、X1、X2、X3、X4、环D、E、Ra、Rb、n和m的含义如规范中所述，它们是RET激酶的抑制剂，并且在治疗和预防可以用RET激酶抑制剂治疗的疾病中非常有用，包括与RET相关的疾病和紊乱。
• [EN] CRYSTALLINE FORMS<br/>[FR] FORMES CRISTALLINES
  申请人：METCALF ANDREW T

  公开号：WO2019075108A1

  公开（公告）日：2019-04-18

  Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which exhibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, the application relates to novel crystalline forms of Formula I-IV and pharmaceutically acceptable salts thereof useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

  本文提供了化合物I-IV及其药学上可接受的盐，这些化合物在转染期间表现出重排（RET）激酶抑制作用。具体来说，本文提供了4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈（化合物I）、6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈（化合物II）、6-(2-羟基-2-甲基丙氧基)-4-(6-(6-(6-甲氧基烟酰基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈（化合物III）、6-(2-羟基-2-甲基丙氧基)-4-(6-(4-羟基-4-(吡啶-2-基甲基)哌啶-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈（化合物IV）及其药学上可接受的盐，包括含有这些化合物的药物组合物、制备这些化合物的方法，以及这些化合物在治疗中的应用。更具体地，本申请涉及化合物I-IV的新晶型及其药学上可接受的盐，用于治疗和预防可以用RET激酶抑制剂治疗的疾病，包括与RET相关的疾病和疾病。
• [EN] SUBSTITUTED PYRAZOLYL[4,3-C]PYRIDINECOMPOUNDS AS RET KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRAZOLYL[4,3-C]PYRIDINE SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA KINASE RET
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2019143994A1

  公开（公告）日：2019-07-25

  Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2 and R3 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

  提供以下式I的化合物：及其互变异构体和药用可接受的盐和溶剂化物，其中R1、R2和R3具有说明书中给出的含义，它们是RET激酶的抑制剂，可用于治疗和预防可通过RET激酶抑制剂治疗的疾病，包括RET相关疾病和失调。