2-[(2S)-7-羰基-2,3-二氢-7H-呋喃并[3,2-g]色烯-2-基]丙烷-2-基β-D-吡喃葡萄糖苷 | 467-82-3

• 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
• 中文名称: 2-[(2S)-7-羰基-2,3-二氢-7H-呋喃并[3,2-g]色烯-2-基]丙烷-2-基β-D-吡喃葡萄糖苷
• 中文别名: 马缨丹烯B
• 英文名称: lantadene B
• 英文别名: 22β-senecioyloxy-3-oxo-olean-12-en-28-oic acid；(4R,4aS,6aR,6aS,6bR,8aR,12aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-4-(3-methylbut-2-enoyloxy)-10-oxo-3,4,5,6,6a,7,8,8a,11,12,13,14b-dodecahydro-1H-picene-4a-carboxylic acid
• CAS: 467-82-3
• 化学式: C₃₅H₅₂O₅
• 分子量: 552.795
• InChiKey: VYPAPFHUHDWCBI-QQAPFUPGSA-N

物化性质

• 沸点：
  626.3±55.0 °C(Predicted)
• 密度：
  1.12±0.1 g/cm3(Predicted)
• 颜色/状态：
  Crystals from ethanol
• 熔点：
  302 °C
• 溶解度：
  In water, 7.68X10-5 mg/L at 25 °C (est)
• 蒸汽压力：
  1.64X10-13 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸钠林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/给豚鼠口服荆芥（Lantana camara var. aculeata）叶粉，剂量为6克/千克体重，引发胆汁郁积。给药后48小时，动物被安乐死。

/LABORATORY ANIMALS: Acute Exposure/ Oral administration of lantana (Lantana camara var. aculeata) leaf powder to guinea pigs at a dose of 6 g/ kg body weight elicited cholestasis. The animals were euthanized 48 hr after dosing.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/从Lantana camara L（红色品种）的叶中通过批量提取和硅胶柱色谱法（60-120目）获得了毒素组分。毒素制剂的主要成分是lantadene A和lantadene B，且不含还原的lantadene A。给雄性和雌性豚鼠口服毒素（125 mg/kg体重）后，48小时内出现了黄疸和光敏反应。所有受影响的动物都有肝肿大，并且血液血浆中的结合和非结合胆红素显著增加。中毒的雄性和雌性动物酸性磷酸酶活性显著增加，分别被1 mM酒石酸抑制了45.77%和49.35%。对照组雄性和雌性豚鼠酸性磷酸酶活性的相应抑制分别为15.91%和20.33%。

/LABORATORY ANIMALS: Acute Exposure/ A toxin fraction was obtained from Lantana camara L (red variety) leaves by batch extraction and column chromatography on silica gel (60-120 mesh). The main constituents of the toxin preparation were lantadene A and lantadene B and it was devoid of reduced lantadene A. Oral administration (125 mg/kg bwt) of the toxin to male and female guinea pigs caused icterus and photosensitization within 48 hr. All the affected animals had hepatomegaly and significant increases in conjugated and unconjugated bilirubin in blood plasma. The intoxicated animals of either sex had marked increases in acid phosphatase activity which was inhibited 45.77% and 49.35% by 1 mM tartrate in male and female animals respectively. The corresponding inhibition of acid phosphatase activity in control male and female guinea pigs was 15.91% and 20.33% respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

豚鼠的肝脏匀浆、胆汁、胆囊、血液、尿液、胃肠道（GIT）内容物和粪便被分析，以检测 Lana 叶中的主要肝毒素，即 Lantadene A（LA）、其同类物和生物转化产物，使用高效液相色谱技术。在肝脏、胆汁、胆囊、血液和尿液中未检测到 Lantadenes。LA 和 Lantadene B（LB）、它们的衍生物还原 Lantadene A（RLA）、还原 Lantadene B（RLB）和两个未识别的代谢物可以在下GIT内容物和粪便中检测到。在体外，将 Lana 叶粉与豚鼠盲肠内容物在无氧条件下孵化，引发了 LA 和 LB 分别向 RLA 和 RLB 的生物转化。另一方面，将 Lana 叶粉与牛瘤胃液在无氧条件下孵化，并未引发 Lantadenes 的生物转化。

/Guinea pig/ liver homogenates, bile, gall bladder, blood, urine, contents of gastrointestinal tract (GIT) and feces were analysed for the principal hepatotoxin in lantana leaves viz. lantadene A (LA), its congeners and biotransformation products, using high performance liquid chromatographic technique. Lantadenes could not be detected in liver, bile, gall bladder, blood and urine samples. LA and lantadene B (LB), their derivatives reduced lantadene A (RLA), reduced lantadene B (RLB) and two unidentified metabolites could be detected in the contents of lower GIT and faeces. In vitro incubation of lantana leaf powder with guinea pig caecal contents under anaerobic conditions elicited biotransformation of LA and LB to RLA and RLB, respectively. On the other hand, incubation of lantana leaf powder with cattle rumen liquor under anaerobic conditions did not elicit biotransformation of lantadenes.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  2-[(2S)-7-羰基-2,3-二氢-7H-呋喃并[3,2-g]色烯-2-基]丙烷-2-基β-D-吡喃葡萄糖苷 在 potassium hydroxide 作用下， 反应 6.0h， 生成 22β-hydroxyoleanonic acid
  参考文献：
  名称：

  The synthesis of non-steroidal anti-inflammatory drug (NSAID)–lantadene prodrugs as novel lung adenocarcinoma inhibitors via the inhibition of cyclooxygenase-2 (COX-2), cyclin D1 and TNF-α-induced NF-κB activation

  摘要：

  强效核因子-kappa B（NF-κB）抑制剂与环氧合酶（COX）抑制性非甾体抗炎药物（NSAIDs）的酯共轭物为癌症治疗提供了一种新颖的方法。合成了不同的NSAIDs与五环三萜类化合物3β，22β-二羟基-油烯-12-烯-28-酸（4）的酯前药，以实现对NF-κB和COX-2的双重抑制。结果表明，主要化合物14通过抑制核因子-kappa B激酶（IKK）的激活，抑制核因子-kappa B alpha（IκBα）的降解，并同时下调NF-κB介导的COX-2和细胞周期蛋白D1的蛋白表达，抑制了肿瘤坏死因子-alpha诱导的（TNF-α诱导的）NF-κB激活。此外，化合物14以剂量依赖的方式抑制肺腺癌A549细胞的增殖，并且其IC50值比顺铂高50倍。化合物14在酸性pH下稳定，而在人体血浆中则容易水解释放活性前体。从结果可以推断，lantadene-NSAID前药具有抑制NF-κB和COX-2的双重能力，有望成为针对肺癌的有前景的抗癌候选药物。

  DOI：

  10.1039/c4ra00280f

文献信息

• Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation
  作者：Monika、Ankesh Sharma、Sharad Kumar Suthar、Vaibhav Aggarwal、Hong Boon Lee、Manu Sharma

  DOI：10.1016/j.bmcl.2014.06.068

  日期：2014.8

  The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.
• Synthesis and in vitro anticancer studies of novel C-2 arylidene congeners of lantadenes
  作者：Navin K. Tailor、Hong L. Boon、Manu Sharma

  DOI：10.1016/j.ejmech.2013.04.009

  日期：2013.6

  The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22 beta-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22 beta-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG_MID) value of compound 3 (MG_MID -5.69) was higher than standard drug cisplatin (MG_MID -5.66) while comparable in case of compound 12 (MG_MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC >= 0.60). (C) 2013 Elsevier Masson SAS. All rights reserved.
• Novel lung adenocarcinoma and nuclear factor-kappa B (NF-κB) inhibitors: Synthesis and evaluation of lantadene congeners
  作者：Sharad Kumar Suthar、Hong L. Boon、Manu Sharma

  DOI：10.1016/j.ejmech.2013.12.052

  日期：2014.3

  The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22 beta hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-kappa B and IKK beta inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 mu mol, respectively against TNF-alpha. induced activation of NF-kappa B. The congeners 12 and 13 exhibited inhibition of IKK beta in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 mu mol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Barton et al., Journal of the Chemical Society, 1954, p. 3689,3691
  作者：Barton et al.

  DOI：——

  日期：——
• Reduced Lantadenes A and B: semi-synthetic synthesis, selective cytotoxicity, apoptosis induction and inhibition of NO, TNF-α production in HL-60 cells
  作者：Suthar Sharad Kumar、Navin Tailor、Hong Boon Lee、Manu Sharma

  DOI：10.1007/s00044-012-0354-x

  日期：2013.7

  The aim of this study was to investigate the effect of pentacyclic triterpenoids-reduced Lantadenes A (3) and B (4) on the cytotoxicity, stimulation of apoptosis and regulation of transcription factors in HL-60 cells. The 3 and 4 are the minor compounds of weed Lantana camara L. (Verbenaceae) and were prepared semi-synthetically in single step by reducing Lantadenes A (1) and B (2) under microwave irradiation with yield of 98-99 %. The 3 and 4 demonstrated selective cytotoxicity against HL-60, MCF-7, HSC-2, and HCT-116 cancer cell lines (IC50 1.2-6.4 mu M) and were found non-toxic toward normal cells (VERO) with IC50 > 50). The compounds 3 and 4 (15 mu M)-induced apoptosis by activation of caspase-3 and bax, along with significant decrease in expression of NF-(DB)-B-0 (p-65) and bcl-2 in HL-60 cells. The compounds 3 and 4 at 15 mu M significantly suppressed the production of nitrite, TNF-alpha, and iNOS gene expression in HL-60 cells. The results suggested that reduced Lantadenes A and B have the potential to be developed as anticancer agents.