蒜黎芦碱 | 469-59-0

• 物质功能分类: 生物化工 - 提取物 - 植物提取物
• 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: 蒜黎芦碱
• 中文别名: 蒜藜芦碱；蒜藜芦碱.介藜芦胺；介芬胺；芥芬胺
• 英文名称: jervine
• 英文别名: (3S,3'R,3'aS,6'S,6aS,6bS,7'aR,9R,11aS,11bR)-3-hydroxy-3',6',10,11b-tetramethylspiro[1,2,3,4,6,6a,6b,7,8,11a-decahydrobenzo[a]fluorene-9,2'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-11-one
• CAS: 469-59-0
• 化学式: C₂₇H₃₉NO₃
• 分子量: 425.612
• InChiKey: CLEXYFLHGFJONT-DNMILWOZSA-N

物化性质

• 熔点：
  242- 244°C
• 比旋光度：
  D20 -150° (ethanol) (Saito); D20 -167.6° (chloroform) (Poethke)
• 沸点：
  541.31°C (rough estimate)
• 密度：
  1.18±0.1 g/cm3 (20 ºC 760 Torr)
• 溶解度：
  溶于甲醇，2mg/mL
• 最大波长(λmax)：
  250nm(lit.)
• 颜色/状态：
  NEEDLES FROM METHANOL + WATER
• 旋光度：
  SPECIFIC OPTICAL ROTATION (ETHANOL): -150 DEG @ 20 °C/D; -167.6 DEG @ 20 °C/D (CHLOROFORM); MAX ABSORPTION: 250, 360 NM (E= 15,000, 60)
• 分解：
  When heated to decomp ... emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  31
• 可旋转键数：
  0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

孵化的小鸡畸形是通过将1-2毫克的环巴胺直接应用于开窗鸡胚的胚胎盾产生的。这表明环巴胺的母体代谢改变并非必要。/PRC：环巴胺是介藜芦碱群成员之一，与介藜芦碱同属一类。/环巴胺/

Malformations in hatched chicks were produced by direct application of 1-2 mg of cyclopamine to the embryonic shield of windowed chicken eggs. This showed that maternal metabolic alteration of cyclopamine was not necessary. /PRC: Cyclopamine is a member of the jerveratum group as is jervine/. /CYCLOPAMINE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

乙酸-1-(14)C、胆固醇-4-(14)C和胆固醇-26-(14)C被引入天仙子碱和藜芦胺中，其标记模式与假设一致，即从EPIRUBIJERVINE衍生出的一个关键中间体通过不同的途径转化为C-去氢-立体甾体生物碱（天仙子碱和藜芦胺）在天仙子中。

INCORPORATION OF ACETATE-1-(14)C, CHOLESTEROL-4-(14)C, & OF CHOLESTEROL-26-(14)C INTO JERVINE & VERATRAMINE GAVE A LABELING PATTERN CONSISTENT WITH THE HYPOTHESIS THAT A KEY INTERMEDIATE DERIVED FROM EPIRUBIJERVINE WAS CONVERTED INTO THE C-NOR-D-HOMOSTEROIDAL ALKALOIDS (JERVINE & VERATRAMINE) BY SEPARATE PATHWAYS IN VERATRUM GRANDIFLORUM.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Jervine的生物学活性是通过与7次跨膜蛋白Smoothened的相互作用来介导的。Jervine与Smoothened结合并抑制它，这是刺猬信号通路的重要组成部分。当Smoothened被抑制时，GLI1转录无法被激活，刺猬靶基因无法被转录。（维基百科）现在已知，Jervine和环丙烯胺的致畸效应是由于它们特异性地抑制了脊椎动物细胞对刺猬（Hh）家族分泌的生长因子的反应。（A15438）在含有环丙烯胺、Jervine或阻断抗体的培养基中，菌状乳头的数量在舌背上增加了一倍，其分布基本上消除了乳头间区域，与标准培养基或茄啶中的舌头相比。（A15439）

Jervine's biological activity is mediated via its interaction with the 7 pass trans membrane protein smoothened. Jervine binds with and inhibits smoothened, which is an integral part of the hedgehog signaling pathways. With smoothened inhibited, the GLI1 transcription cannot be activated and hedgehog target genes cannot be transcribed. (Wikipedia) It is now known that the teratogenic effects of jervine and cyclopamine are due to their specific inhibition of vertebrate cellular responses to the Hedgehog (Hh) family of secreted growth factors. (A15438) In cultures with cyclopamine, jervine, or blocking antibody, fungiform papilla numbers doubled on the dorsal tongue with a distribution that essentially eliminated inter-papilla regions, compared with tongues in standard medium or solanidine. (A15439)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 副作用

神经毒素 - 其他中枢神经系统神经毒素

Neurotoxin - Other CNS neurotoxin

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 人类毒性摘录

几种马兜铃属植物与人类和动物的毒性有关。主要毒素是甾体生物碱；有些具有改性的甾体模板，而其他则在于它们的酯化酸部分不同。这些生物碱通过增加神经细胞钠通道的通透性，使它们持续放电。与迷走神经相关联的刺激增加导致被称为贝佐尔德-雅里施反射的三联反应：低血压、心动过缓和呼吸暂停。临床上，各种马兜铃提取物被作为抗高血压药物上市，但由于治疗指数狭窄而被撤出市场。摄入马兜铃生物碱后，预期的体征和症状包括呕吐和腹痛，随后出现心血管效应，如心动过缓、低血压和心脏传导异常甚至死亡。其他哺乳动物摄入这些生物碱后也会出现类似的症状；食用加州马兜铃的动物胎儿可能会出现致畸效应。治疗包括支持性护理，重点是使用液体置换、阿托品和血管加压药来维持血流动力学稳定。症状出现时间在30分钟到4小时之间，病程可能从1天到10天不等；然而，在及时的支持性护理下，患者通常在24小时内完全恢复。

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnea. Clinically, various Veratrum extracts were marketed for use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on hemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

加州藜芦在20世纪50年代导致爱达荷州中部高山区放牧的羊群遭受重大损失。藜芦会引起各种出生缺陷，包括在怀孕母羊在妊娠第14天食用该植物后，在羊羔中特异性诱导的 cyclopic-type 颅面缺陷（猴面羊羔）。从藜芦中分离出的甾体生物碱环菠萝胺（1）和藜芦碱（2）被证明是导致这些畸形的主要物质。环菠萝胺（1）和藜芦碱（2）是强烈的致畸剂，它们在胚胎发育的胚层形成阶段抑制音猬因子（Shh）信号传导，导致独眼畸形和全前脑畸形。尽管目前藜芦对羊产业造成的损失相对较少，但在羊和其他物种中偶尔还会报告有毒性疾病和颅面畸形的事件...

Veratrum californicum was responsible for large losses of sheep grazing high mountain ranges in central Idaho in the 1950s. Veratrum induces various birth defects including the cyclopic-type craniofacial defect (monkey-faced lambs) that is specifically induced in lambs after pregnant ewes grazed the plant on the 14th day of gestation. The steroidal alkaloids cyclopamine (1) and jervine (2) were isolated from Veratrum and shown to be primarily responsible for the malformations. Cyclopamine (1) and jervine (2) are potent teratogens that inhibit Sonic hedgehog (Shh) signaling during gastrulation-stage embryonic development, producing cyclopia and holoprosencephaly. Although losses to the sheep industry from Veratrum are now relatively infrequent, occasional incidents of toxicoses and craniofacial malformations are still reported in sheep and other species...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xn
• 危险类别码：
  R22
• 危险品运输编号：
  UN 2811 6.1/PG 3
• WGK Germany：
  3
• RTECS号：
  WG9700000
• 危险标志：
  GHS06
• 危险性描述：
  H301
• 危险性防范说明：
  P301 + P310

制备方法与用途

生物活性

Jervine（11-Ketocyclopamine）是Hedgehog信号通路的抑制剂（IC50=500-700 nM），通过与smoothened相互作用抑制shh信号通路。

靶点

Target	Value
Hedgehog
Shh

体外研究

相比于对照组，暴露于25 μg/ml Jervine的软骨细胞在数量上明显减少，但在形态或阿尔新蓝染色强度方面没有变化。

体内研究

Jervine暴露会导致胚胎出现颅面骨畸形，与Shh突变胚胎表型类似。这些胚胎下颌显著减小，通常导致门齿缺失。对受孕小鼠处理后，其胚胎会表现出颌骨缺损的表型，类似于Prx1基因缺陷。

化学性质

Jervine是一种白色结晶粉末，可溶于甲醇、乙醇和DMSO等有机溶剂，来源于藜芦。

反应信息

• 作为反应物：
  描述：

  蒜黎芦碱 在 氢氧化钾 、 一水合肼 作用下， 以51%的产率得到环巴胺
  参考文献：
  名称：

  Jervine 转化为 18-Functional C-Nor-D-homosteroids

  摘要：

  N,O-Diacetyldeoxojervine 是通过 Wolff-Kishner 还原 jervine 然后乙酰化获得的，已催化氢化为 (22S,25S)-N,3-O-diacetyl-5α-veratranine-3β,3β-diol。在含汞 (II) 氧化物和碘的苯中照射，得到 20-formyl-17β-ethyl-12α-etiojervan-3β-ol 3-acetate，然后转化为 17β-ethyl-3β-hydroxy-12α-etiojervan-20-one 3 -通过相应吗啉烯胺的染料敏化光氧化作用生成乙酸盐。用硼氢化钠将 17β-乙基-12α-etiojervane-3β,20β-diol 3-acetate 还原为 17β-ethyl-12α-etiojervane-3-acetate，然后在氧化汞 (II) 和碘存在下在苯中进行辐照，得到 18 功能的 C-nor-D-同质甾体，

  DOI：

  10.1246/bcsj.53.210
• 作为产物：
  描述：

  (23R)-28-acetyl-17,23-epoxy-3β-hydroxy-(5α)-veratr-12-en-11-one 在 钯 chromium(VI) oxide 、 氢氧化钾 、 sodium tetrahydroborate 、 氢气 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 生成 蒜黎芦碱
  参考文献：
  名称：

  C-Nor-D-homosteroids and related alkaloids. IX. Synthesis of jervine and related alkaloids

  摘要：

  DOI：

  10.1021/ja00993a048

文献信息

• [EN] 1,2,4-OXADIAZOLE SUBSTITUTED PIPERIDINE AND PIPERAZINE DERIVATIVES AS SMO ANTAGONISTS<br/>[FR] DÉRIVÉS DE PIPÉRIDINE OU PIPÉRAZINE SUBSTITUÉS PAR 1,2,4-OXADIAZOLE COMME ANTAGONISTES DE SMO
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2010013037A1

  公开（公告）日：2010-02-04

  The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts, stereoisomers or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smo antagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及式(I)的化合物及其药学上可接受的盐、立体异构体或互变异构体，这些化合物是Sonic Hedgehog途径的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物对治疗与异常Hedgehog途径激活相关的疾病有用，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌，以及上消化道的癌症。
• HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
  申请人：Ivaschenko Andrey Alexandrovich

  公开号：US20110053915A1

  公开（公告）日：2011-03-03

  The invention relates to novel heterocyclic compounds and to the use thereof, to pharmaceutical compositions containing said chemical compounds as an active ingredient and to the use thereof for producing medicinal preparations for the human being and warm-blood animals for treating diseases caused by the aberrant activity of an Hedgehog (Hh)-signal system, in particular oncological diseases. The invention also relates to the use of the above-mentioned compounds in the form of ‘molecular pharmacological tools’ for examining (in vitro and in vivo) the biochemical features of the Hh-signal system, in particular, the interaction of Hh protein and transmembrane proteins, namely, suppressor Patched (Ptc) and protooncogenic proteins. The eight groups of the claimed compounds comprise the derivatives of 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazine-7-one and 1,4-dihydropyrazolo[3,4-b][1,4]thiazine-5-one; N-acidylated 4-imidazo[1,2-a]pyrimidine-2-il-anilines; ([4H-thino[3,2-b]pyrrol-5-il) carbonyl]piperidine-4-carbonic acid amides; 2-(4carbomoilpyperidine-1-il)-isonicotinic acid amides; N-sylphonyl-1,2,3,4-tetrahydroquinoline-6-carbonic acid amides; and pyridine 2-amino-4,5,6,7-tetrahydrothieno[2,3-c] N-acidylated 3-azole derivatives.

  该发明涉及新颖的杂环化合物及其用途，包括含有该化合物作为活性成分的药物组合物，以及用于制备用于治疗由Hedgehog（Hh）信号系统异常活性引起的人类和温血动物疾病的药物制剂。该发明还涉及上述化合物的使用形式为“分子药理学工具”，用于检查Hh信号系统的生化特征（体外和体内），特别是Hh蛋白与跨膜蛋白之间的相互作用，即抑制剂Patched（Ptc）和原癌基因蛋白。所述化合物的八个类别包括2,6-二氢-7H-吡唑并[3,4-d]吡啶嗪-7-酮和1,4-二氢吡唑并[3,4-b][1,4]噻嗪-5-酮的衍生物；N-酰化的4-咪唑并[1,2-a]嘧啶-2-基-苯胺；([4H-噻吩[3,2-b]吡咯-5-基)羰基]哌啶-4-羧酸酰胺；2-(4-羧甲基哌啶-1-基)-异尼古丁酸酰胺；N-磺酰基-1,2,3,4-四氢喹啉-6-羧酸酰胺；以及吡啶2-氨基-4,5,6,7-四氢噻吩[2,3-c] N-酰化的3-唑衍生物。
• [EN] MODULATORS OF HEDGEHOG (HH) SIGNALLING PATHWAY<br/>[FR] MODULATEURS DE LA VOIE DE SIGNALISATION HEDGEHOG (HH)
  申请人：E THERAPEUTICS PLC

  公开号：WO2018078360A1

  公开（公告）日：2018-05-03

  There are described compounds of formula (I): and there use as a medicament in the treatment of conditions involving abnormal activation and/or malfunction of the of the hedgehog pathway, such as cancer, fibrosis and chronic graft-versus-host disease (cGVHD).

  描述了化合物的结构式(I)：以及它们在治疗涉及Hedgehog通路异常激活和/或功能失调的疾病中的用途，如癌症、纤维化和慢性移植物抗宿主病（cGVHD）的药物。
• [EN] UNSATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES BICYCLIQUES INSATURÉS UTILISÉS COMME ANTAGONISTES DE SMO
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2010082044A1

  公开（公告）日：2010-07-22

  The present invention relates to compounds of formula (I); and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smo antagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及式(I)的化合物；以及其药用可接受的盐或互变异构体，它们是Sonic Hedgehog途径的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物可用于治疗与异常刺刺途径激活相关的疾病，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌，以及上消化道癌。
• [EN] SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES BICYCLIQUES SATURÉS EN TANT QU'ANTAGONISTES DE SMO
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2010023480A1

  公开（公告）日：2010-03-04

  The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及公式I的化合物及其药用可接受的盐或互变异构体，这些化合物是Sonic Hedgehog通路的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物可用于治疗与异常刺刺通路激活相关的疾病，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌，以及上消化道癌症。