黄连碱 | 3486-66-6

• 物质功能分类: 生物化工 - 中草药成分
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 原小檗碱生物碱及其衍生物
• 中文名称: 黄连碱
• 中文别名: 硫酸黄连碱；小檗碱
• 英文名称: coptisine
• 英文别名: coptisin；5,7,17,19-tetraoxa-13-azoniahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(13),2,4(8),9,14,16(20),21,23-octaene
• CAS: 3486-66-6
• 化学式: C₁₉H₁₄NO₄
• 分子量: 320.324
• InChiKey: XYHOBCMEDLZUMP-UHFFFAOYSA-N

物化性质

• 熔点：
  212-217 °C
• 溶解度：
  溶于氯仿、二氯甲烷、乙酸乙酯、DMSO、丙酮等。
• 蒸汽压力：
  1.12X10-9 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions. /Coptisine chloride/

• 分解：
  When heated to decomposition it emits toxic vapors of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  40.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

毒理性

• 毒性总结

鉴定和使用：黄连素是一种在中国黄连中发现的细胞毒性生物碱，与黄连碱相关。它用于生化研究，并已被测试为实验性治疗。人类暴露和毒性：对黄连素进行了细胞毒性的评估，对象是一组人类和小鼠细胞系，与已建立的抗肿瘤药物米托蒽醌、多柔比星（Dx）和顺铂（CDDP）进行比较。黄连素对LoVo和HT-29具有细胞毒性，对L-1210的效力较低，而在对Dx耐药的人类肿瘤结肠细胞系LoVo/Dx上部分交叉耐药，而在对CDDP耐药的小鼠白血病细胞系L-1210/CDDP上则没有显著的交叉耐药性。黄连素在较低浓度下可选择性地预防血管平滑肌细胞的增殖，与其他各种细胞或结构相关的生物碱相比。黄连素具有降低胆固醇的潜在药理活性，可能通过调节参与胆固醇代谢的关键基因的mRNA和蛋白表达来降低胆固醇，如LDLR、CYP7A1和HMGCR。动物研究：黄连素是A型单胺氧化酶的一种强效可逆抑制剂。黄连素抑制血管平滑肌细胞的增殖。在亚慢性毒性研究中，没有观察到可能与黄连素治疗相关的死亡和疾病。此外，在口服黄连素后，任何动物的临床症状、体重、器官重量、尿检、血液学参数、大体解剖和病理学都没有异常。

IDENTIFICATION AND USE: Coptisine, a cytotoxic alkaloid found in Chinese goldthread, is related to berberine. It is used in biochemical studies and has been tested as experimental therapy. HUMAN EXPOSURE AND TOXICITY: Cytotoxicity evaluation of coptisine was conducted on a panel of human and murine cell lines in comparison with the established antitumor drugs mitoxantrone, doxorubicin (Dx), and cisplatin (CDDP). Coptisine was cytotoxic on LoVo and HT-29 and less potent on L-1210, and it was partially crossresistant on the human tumor colon cell line resistant to Dx, LoVo/Dx, whereas it was not significantly crossresistant on the murine leukemia cell line resistant to CDDP, L-1210/CDDP. Coptisine prevents vascular smooth muscle cell proliferation selectively at lower concentrations compared with various cells or other structurally related alkaloids. Coptisine has potential pharmacological activity for reducing cholesterol, and may reduce cholesterol by regulating mRNA and protein expressions of key genes involved in cholesterol metabolism, such as LDLR, CYP7A1, and HMGCR. ANIMAL STUDIES: Coptisine is a potent reversible inhibitor of type A monoamine oxidase. Coptisine inhibits proliferation of vascular smooth muscle cells. In the sub-chronic toxicity study, no mortality and morbidity were observed which could be related to coptisine treatment. Besides, there was no abnormality in clinical signs, body weights, organ weights, urinalysis, hematological parameters, gross necropsy, and histopathology in any of the animals after the oral administration of coptisine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球阀口罩装置或口袋口罩，按培训操作。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，让患者向前倾或放在左侧（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。 /毒药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 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。使用气囊阀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受体激动剂，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5%葡萄糖水（D5W），并暂停其他输注。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意观察液体过载的迹象……。使用地西泮（安定）或劳拉西泮（安定文）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 TKO. Use 0.9% saline (NS) or lactated Ringer's (LR) 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 (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

这段文字讨论了毛茛草（Chelidonii herba）提取物对卤虫（Artemia salina Leach）无节幼体和体外培养的人类肿瘤细胞（结肠癌HT 29细胞系）的细胞毒性。通过提取物的分馏和生物活性指导程序，发现细胞毒性和抗肿瘤活性主要集中在碱性提取物中。通过红外光谱、质谱和核磁共振氢谱分析，确定了负责细胞毒活性的化合物是黄连碱（coptisine）。接下来，将黄连碱的细胞毒性评估扩展到了一系列人类和小鼠细胞系，并与已建立的抗肿瘤药物米托蒽醌、阿霉素（Dx）和顺铂（CDDP）进行了比较。黄连碱对LoVo和HT-29细胞系具有细胞毒性，对L-1210细胞系的活性较弱，并且对人类肿瘤结肠细胞系LoVo/Dx的阿霉素抗性具有一定的交叉抗性，而对小鼠白血病细胞系L-1210/CDDP的顺铂抗性没有显著的交叉抗性。随后，从商用黄连碱合成了克级的黄连碱生物碱。制定了一个四步合成路线。总收率约为8-10%。通过红外光谱和核磁共振方法验证了合成黄连碱的结构同一性。对人类肿瘤结肠细胞系LoVo和小鼠白血病细胞系L-1210的细胞毒性效果比较显示，无论是天然的还是合成的黄连碱，对HT-29和LoVo细胞系的细胞毒性活性相当显著，而对L-1210细胞系的活性较低。

/ALTERNATIVE and IN VITRO TESTS/ The crude extract (80% MeOH in water) of Chelidonii herba exhibited very interesting cytotoxicity against brine shrimp (Artemia salina Leach) nauplii and cultured human tumor cell in vitro, the colon carcinoma HT 29 (144 hr treatment). Fractionation of the crude extract and bioassay-guided procedures showed that the cytotoxic and the antitumor activities were concentrated in the basic extract. On the basis of IR, MS, and (1)H NMR the compound responsible of the cytotoxic activity was determined to be coptisine. Cytotoxicity evaluation of coptisine was next extended to a panel of human and murine cell lines in comparison with the established antitumor drugs mitoxantrone, doxorubicin (Dx) and cisplatin (CDDP). Coptisine was cytotoxic on LoVo and HT-29 and less potent on L-1210, and it was partially crossresistant on the human tumor colon cell line resistant to Dx, LoVo/Dx, whereas it was not significantly crossresistant on the murine leukemia cell line resistant to CDDP, L-1210/CDDP. Coptisine alkaloid was then synthesized in gram amount from commercial berberine. A four-step synthetic route was elaborated. The overall yield was about 8-10%. The structural identity of synthetic coptisine was verified by IR and NMR methods. A comparison of the cytotoxic effects on the human tumor colon cell line LoVo and on the murine leukemia L-1210 showed, for both natural and synthetic coptisines, a comparable cytotoxic activity more evident against HT-29 cell line and LoVo cell line, while the activity was lower against the L-1210 cell line.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

延胡索乙素（岩黄连）是传统中医药方中的重要组成部分。岩黄连已被证实具有多种药理活性，包括抗菌、抗病毒和抗癌活性。其中的活性成分包括去氢鸦片碱、黄连碱、去氢阿朴鸦片碱和四去氢苦参碱。本次研究的目的通过使用高效液相色谱（HPLC）与串联质谱技术来研究在大鼠体内的药代动力学和组织分布。四种活性生物碱在血浆中的系统清除率超过93%的肝血流量，表明它们可能通过肝脏清除而被迅速消除。静脉和口服给药后通过尿液排出的药物不到10%，这表明这四种生物碱可能在体内发生显著代谢，或者药物可能通过尿液以外的其他途径排出。口服给药后这四种生物碱的排泄量显著低于静脉给药，这表明口服给药后存在显著的首过效应。这四种生物碱在大鼠体内的分布似乎很广泛，因为表观分布体积较高。我们的结果还表明，尽管少于15%的药物被吸收进入系统循环，但这四种生物碱可以在口服给药后被吸收。总之，这四种活性生物碱在大鼠体内的有利口服生物利用度特性使得岩黄连提取物值得进一步研究以提高口服生物利用度。

Corydalis saxicola Bunting (Yanhuanglian) is an important component in various prescriptions in traditional Chinese medicine. Yanhuanglian has been demonstrated to possess many pharmacological activities, including antibacterial, antiviral, and anticancer activities. The active fractions are dehydrocavidine, coptisine, dehydroapocavidine, and tetradehydroscoulerine. The purpose of the present study was to examine in vivo pharmacokinetics and tissue distribution in rats by using high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry. Systemic clearance of the four active alkaloids in plasma was over 93% of hepatic blood flow, indicating they may be quickly eliminated via hepatic clearance. Less than 10% drugs was excreted via urine following intravenous and oral administration, suggesting that these four alkaloids may undergo significant metabolism in the body or the drug may be excreted via other routes other than urine. There was significantly lower excretion of these four alkaloids following oral than intravenous administration, suggesting a significant first pass effect after oral administration. There appeared to be wide distribution of those four alkaloids in rats as demonstrated by the higher apparent volume of distribution. Our results have also demonstrated that the four alkaloids can be absorbed following oral administration although there were less than 15% of drugs absorbed into systemic circulation. In summary, the favorable oral bioavailability properties of those four active alkaloids in rats make Yanhuanglian extract worth further investigation for improving oral bioavailability.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究黄连素氯化物（COP）和小檗红碱（BRB）作为某些传统中药的化学成分在人肠上皮细胞中的吸收情况。通过使用Caco-2（人结肠腺癌细胞系）细胞单层作为肠上皮细胞模型，研究了COP和BRB从顶端侧（AP侧）到基底侧（BL侧）或从BL侧到AP侧的通透性。这两种生物碱通过反相高效液相色谱（HPLC）与紫外检测器相结合进行测量。然后计算并比较了运输参数和表观通透性系数（P(app)），与普罗帕酮和阿替洛尔的相关参数进行了比较。P(app)值也与报告的模型化合物（普罗帕酮和阿替洛尔）的值进行了比较。COP、BRB的P(app)值分别为(1.103 +/- 0.162) x 10(-5)和(1.309 +/- 0.102) x 10(-5) cm x s(-1)从AP侧到BL侧，以及(0.300 +/- 0.041) x 10(-5)和(1.955 +/- 0.055) x 10(-5) cm x s(-1)从BL侧到AP侧，分别为。它们的P(app)值与普罗帕酮[(2.23 +/- 0.10) x 10(-5) cm x s(-1)]相同，普罗帕酮是一种跨细胞运输标记，作为高通透性的控制物质。另一方面，BRB的外排运输比其内流运输高出1.49倍，P(app A-->B)/P(app B-->A)的速率为0.67。但COP的P(app A-->B)/P(app B-->A)值为3.67，这表明外排运输并未涉及其在Caco-2细胞单层中的吸收机制。COP和BRB可以跨过肠上皮细胞被吸收，并且它们是完全被吸收的化合物。BRB可能涉及Caco-2细胞单层模型从基底侧到顶端侧的外排机制。

To study the absorption of coptisine chloride (COP) and berberrubine (BRB) as chemical constituents of some traditional Chinese medicines in human intestinal epithelial. By using Caco-2 (the human colonic adenocarcinoma cell lines) cell monolayers as an intestinal epithelial cell model, the permeability of COP and BRB were studied from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. The two alkaloids were measured by reversed-phase high performance liquid chromatography (HPLC) coupled with UV detector. Transport parameters and apparent permeability coefficients (P(app)) were then calculated and compared with those of propranolol and atenolol. P(app) values were also compared with the reported values for model compounds (propranolol and atenolol). The P(app) values of COP, BRB were (1.103 +/- 0.162) x 10(-5), (1.309 +/- 0.102) x 10(-5) cm x s(-1 from AP side to BL side, and (0.300 +/- 0.041) x 10(-5) and (1.955 +/- 0.055) x 10(-5) cm x s(-1) from BL side to AP side, respectively. Their P(app) values were identical with those of propranolol [(2.23 +/- 0.10) x 10(-5 cm x s(-1)], which is a transcellular transport marker and as a control substance for high permeability. On the other hand, the efflux transport of BRB was higher 1.49 times more than its influx transport with 0.67 rate of P(app A-->B)/P(app B-->A). But P(app A-->B)/P(app B-->A value of COP was 3.67, which suggested that the efflux transport have not been involved in its absorbed mechanism in Caco-2 cells monolayers. COP and BRB can be absorbed across intestinal epithelial cells, and they are completely absorbed compounds. BRB may have been involved in efflux mechanism in Caco-2 cells monolayers model from the basolateral-to-apical direction.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了确定黄连中总生物碱、药根碱、黄连碱、小檗碱和巴马汀在大鼠体内的药代动力学、分布和相互转化情况。在给大鼠喂食总生物碱和小檗碱后，通过反相高效液相色谱法测定它们在血浆、组织和胃肠道中的含量。小檗碱在血液中的峰时间分别为2.0小时（Cmax 3.7 mg x L(-1)）和5.0小时（Cmax 2.8 mg x L(-1)）。大鼠血液中的小檗碱可以转化为药根碱。在大鼠灌胃总生物碱后，小檗碱的含量单调减少，而黄连碱、巴马汀和药根碱的含量在胃中逐渐增加，推测小檗碱可能在胃中转化为药根碱。动物实验表明，小檗碱和巴马汀主要分布在动物的肺中，其次是肝脏，而药根碱和黄连碱主要分布在肝脏，然后是肺。小檗碱可以转化为药根碱。血液中小檗碱出现两个最大血药浓度的机制可以用胃肠道的推动部分来解释。

To determine the pharmacokinetics, distribution, and mutual transformation of the total alkaloids, jatrorrhizine, coptisine, berberine, and palmatine from Coptis chinensis in rats. After the total alkaloids and berberine were fed into rats, their contents in plasma, tissues and gastrointestinal tract were determined by reversed-phase HPLC. The peak times of berberine in blood were 2.0 hr (Cmax 3.7 mg x L(-1)) and 5.0 hr Cmax 2.8 mg x L(-1)), respectively. Berberine in rat blood can be transformed into jatrorrhizine. After the rats were fed with the total alkaloids by gavage, the content of berberine was decreased monotonously, while coptisine, palmatine, and jatrorrhizine contents were increased gradually in the stomach, it speculated that berberine may be transformed into jatrorrhizine in the stomach. Animal experiments showed that berberine and palmatine were mainly distributed in the lungs of animals, followed by the distribution in the liver, while jatrorrhizine and coptisine was mainly in the liver, then in the lungs. Berberine could transform into jatrorrhizine. The mechanism on the appearance of two maximum blood concentration of berberine in blood could be explained with the propulsion of the gastrointestinal tract partly.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

使用Caco-2细胞摄取和转运模型研究了小檗碱、巴马汀、黄连碱和黄连素的吸收和转运机制，同时添加了环孢素A和维拉帕米作为P-糖蛋白（P-gp）的抑制剂，以及MK-571作为多药耐药相关蛋白2（MRP(2)）的抑制剂。在摄取实验中，小檗碱、巴马汀、黄连碱和黄连素都被Caco-2细胞摄取，并且在与环孢素A或维拉帕米存在时它们的摄取增加了。在转运实验中，小檗碱、巴马汀、黄连碱和黄连素的P(app) (AP-BL)值介于0.1和1.0 x 10(6) cm/sec之间，低于P(app) (BL-AB)值。ER值均大于2。环孢素A和维拉帕米都增加了小檗碱、巴马汀、黄连碱和黄连素的P(app) (AP-BL)，但减少了P(app) (BL-AB)；ER值降低了超过50%。MK-571对小檗碱、巴马汀、黄连碱和黄连素的跨膜转运没有影响。在1-100 uM的浓度下，小檗碱、巴马汀、黄连碱和黄连素对Rho123的双向转运没有显著影响。小檗碱、巴马汀、黄连碱和黄连素都是P-gp的底物；在1-100 uM的范围内，小檗碱、巴马汀、黄连碱和黄连素对P-gp没有抑制作用。

The absorption and transport mechanisms of berberine, palmatine, jateorhizine, and coptisine were studied using a Caco-2 cells uptake and transport model, with the addition of cyclosporin A and verapamil as P-glycoprotein (P-gp) inhibitors and MK-571 as a multidrug resistance-associated protein 2 (MRP(2)) inhibitor. In the uptake experiment, berberine, palmatine, jateorhizine, and coptisine were all taken into Caco-2 cells, and their uptakes were increased in the presence of cyclosporin A or verapamil. In the transport experiment, P(app) (AP-BL) was between 0.1 and 1.0 x 10(6) cm/sec for berberine, palmatine, jateorhizine, and coptisine and was lower than P(app) (BL-AB). ER values were all >2. Cyclosporin A and verapamil both increased P(app) (AP-BL) but decreased P(app) (BL-AB) for berberine, palmatine, jateorhizine, and coptisine; ER values were decreased by >50%. MK-571 had no influence on the transmembrane transport of berberine, palmatine, jateorhizine, and coptisine. At a concentration of 1-100 uM, berberine, palmatine, jateorhizine, and coptisine had no significant effects on the bidirection transport of Rho123. Berberine, palmatine, jateorhizine, and coptisine were all P-gp substrates; and at the range of 1-100 uM, berberine, palmatine, jateorhizine, and coptisine had no inhibitory effects on P-gp.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

交泰丸（JTW）是一种重要的中药配方，由黄连和肉桂粉组成，是中医药治疗失眠的著名处方，已经使用了数个世纪。本研究的目的是比较正常和失眠大鼠之间交泰丸中五种原小檗碱型生物碱（即小檗碱、巴马汀、黄连碱、表小檗碱和药根碱）的药代动力学特性，这些是JTW中的主要生物活性成分。我们还调查了五种原小檗碱型生物碱单次给药和多次给药药代动力学的差异。失眠大鼠模型通过腹腔注射一次剂量的对氯苯丙氨酸酸（PCPA）诱导。使用快速LC-MS/MS方法对大鼠血浆中的五种原小檗碱型生物碱进行定量。在不同时间点收集血浆样本，通过绘制药物浓度与时间的关系图来构建药代动力学曲线，并估计药代动力学参数。使用SPSS 17.0进行非配对学生t检验比较。正常组单次给药的五种原小檗碱型生物碱吸收缓慢，生物利用度低，且达峰时间延迟。在单次口服给药中，失眠大鼠的五种成分的Cmax和Tmax与正常大鼠相比有显著差异。在多次口服给药中，失眠大鼠的五种原小檗碱型生物碱的药代动力学参数变化很大。在正常大鼠中，单次给药和多次给药的口服给药主要药代动力学参数（如Cmax和Tmax）之间存在显著差异（p<0.05）。在失眠大鼠中，多次给药组的五种成分吸收优于单次给药组。特别是在多次给药模型组的血浆浓度曲线中观察到了三个峰。本文描述了五种原小檗碱型生物碱的药代动力学行为。在正常组和模型组中，多次给药的药代动力学行为与单次给药有显著差异；无论是单次给药还是多次给药，失眠大鼠的药代动力学行为与正常大鼠有显著差异。多次给药可能改善失眠大鼠对JTW的吸收，这将增加生物利用度并使其在治疗效果中发挥积极作用。

Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine. The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine-type alkaloids. The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC-MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters. An unpaired Student's t test was used for comparisons with SPSS 17.0. The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the Cmax and Tmax of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences (p<0.05) in the principal pharmacokinetic parameters such as Cmax and Tmax between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma-concentration curves. The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  SA
• 储存条件：
  室温

制备方法与用途

生物活性

Coptisine是从黄连中分离得到的生物碱，是一种有效的非竞争性IDO抑制剂，其Ki值为5.8 μM，IC50值为6.3 μM。

目标

• IDO
  • IC50: 6.3 μM
  • Ki: 5.8 μM

体外研究

Coptisine是一种高效的非竞争性IDO抑制剂，其Ki值为5.8 μM，IC50值为6.3 μM。在不同浓度（0.1-100 μM）下，Coptisine能够抑制A549、H460、H2170、MDA-MB-231和HT-29细胞的增殖，各细胞系的IC50分别为18.09、29.50、21.60、20.15和26.60 μM。在浓度依赖性下，Coptisine可上调pH2AX和p21表达，降低cyclin B1、cdc2和cdc25C的表达，并诱导A549细胞G2/M期阻滞及凋亡。此外，Coptisine还导致线粒体功能障碍并激活半胱氨酸蛋白酶活性，在A549细胞中表现出浓度依赖性ROS水平增加（0.5、1、2、4、12和24小时）。

体内研究

在小鼠中的毒性表现为剂量依赖性，其LD50值为880.18 mg/kg。Coptisine以154 mg/kg/天的剂量连续给SD大鼠90天未表现出毒性。Coptisine不同剂量（23.35、46.7、70.05 mg/kg，口服）能够不同程度地降低血清中的总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-c)，同时增加高密度脂蛋白胆固醇(HDL-c)含量。在高脂肪饮食诱导的体重增加中，Coptisine表现出剂量依赖性减缓，并能增加粪便中胆固醉和TBA水平。

化学性质

• 极略微溶于水
• 微溶于乙醇
• 溶于碱
• 来源：罂粟科植物白屈菜根

用途

用于含量测定/鉴定/药理实验等。
药理作用：具有抗微生物活性，对抗卡尔酵母菌的效力比小檗碱、巴马汀及非洲防己碱更强；杀虫活性；诱导神经细胞分化；对胃粘膜有保护作用；抗癌作用；免疫系统的作用；平滑肌松弛作用；抗肾炎作用。

反应信息

• 作为反应物：
  描述：

  黄连碱 在 potassium hydroxide 作用下， 反应 8.0h， 以28 mg的产率得到8-氧代黄连碱; 8-氧黄连碱
  参考文献：
  名称：

  Design, Synthesis and Multidrug Resistance Reversal Activity Evaluation of 8-Oxocoptisine Derivatives

  摘要：

  基于8-氧代黄连碱具有强效逆转作用，制备了15种8-氧代黄连碱衍生物 对抗具有多重耐药性（MDR）的人类癌细胞。评估衍生品的增长 对 MCF-7/AMD 细胞的抑制和逆转 P-gp 介导的 MDR 的影响。 12, 13-二硝基-8-氧代槐碱 (6c), 最有潜力的候选者，生长抑制较弱，显着提高阿霉素（ADM）的敏感性 10μM 浓度下，对 MCF-7/ADM 细胞的抑制作用增强了 213 倍，与参考化合物维拉帕米相当。初步的 在体外 MDR 逆转的基础上讨论了这些衍生物的构效关系（SAR） 活动。

  DOI：

  10.2174/157340612801216148
• 作为产物：
  描述：

  小檗碱 生成 黄连碱
  参考文献：
  名称：

  Hanaoka, Miyoji; Sakurai, Shun-ichiro; Ohshima, Takeshi, Chemical and pharmaceutical bulletin, 1982, vol. 30, # 9, p. 3446 - 3449

  摘要：

  DOI：

文献信息

• [EN] PYRAZOLO[3,4-b]PYRIDINE COMPOUNDS AS INHIBITORS OF TAM AND MET KINASES<br/>[FR] COMPOSÉS PYRAZOLO[3,4-B]PYRIDINE UTILISÉS EN TANT QU'INHIBITEURS DE KINASES TAM ET MET
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2020047184A1

  公开（公告）日：2020-03-05

  Provided herein are compounds of the Formula (I): and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R9, X1 and G are as defined herein, which are inhibitors of one or more TAM kinases and/or c-Met kinase, and are useful in the treatment and prevention of diseases which can be treated with a TAM kinase inhibitor and/or a c-Met kinase inhibitor.

  本文提供了Formula (I)的化合物及其立体异构体、互变异构体和药学上可接受的盐，其中R1、R2、R9、X1和G如本文所定义，它们是一种或多种TAM激酶和/或c-Met激酶的抑制剂，并且在治疗和预防可以用TAM激酶抑制剂和/或c-Met激酶抑制剂治疗的疾病中非常有用。
• COMPOUNDS, COMPOSITIONS AND METHODS FOR REDUCING LIPID LEVELS
  申请人：Liu Haiyan

  公开号：US20090048246A1

  公开（公告）日：2009-02-19

  Compositions comprising extracts or isolated or purified compounds from plants of the genus Corydalis provide prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Corydalis compounds and their derivatives of natural and synthetic origins lower total cholesterol, LDL-cholesterol, and triglycerides and increase hepatic LDL receptor expression and activate AMP-activated protein kinase. Specific stereoisomers of Corydalis compounds with lipid lowering activity include 14R-(+)-corypalmine, 14R,13S-(+)-corydaline, 14R-(+)-tetrahydropalmatin, (+)-corlumidin, d-(+)-bicuculline, and (+)-egenine.

  从黄堇属植物提取物或分离纯化的化合物构成的组合物可预防和治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性和代谢综合征。黄堇化合物及其天然和合成来源的衍生物可降低总胆固醇、LDL-胆固醇和甘油三酯，增加肝LDL受体表达并激活AMP激活蛋白激酶。具有降脂活性的黄堇化合物的特定立体异构体包括14R-(+)-可丹碱、14R,13S-(+)-可丹啉、14R-(+)-四氢棕榈碱、(+)-可鲁米丁、d-(+)-比库枯碱和(+)-艾根碱。
• Derivatives Of Protoberberine Biological Alkaloids And Use Of Same Inhibiting Ulcerative Colitis
  申请人：Institute of Materia Medica, Chinese Academy of Medical Sciences

  公开号：US20150031717A1

  公开（公告）日：2015-01-29

  Disclosed are derivatives of protoberberine biological alkaloids or physiologically acceptable salts thereof produced by means of a derivative reaction of a source material of biological alkaline quaternary ammonium salts of protoberberine alkaloids, a preparation method for same and pharmaceutical uses thereof. The derivatives of protoberberine biological alkaloids or the physiologically acceptable salts thereof show activity inhibiting ulcerative colitis and can be used in the preparation of drugs for same.

  本文披露了通过对原生物碱类季铵盐的源材料进行衍生反应而产生的原生物碱类季铵盐的衍生物或其生理上可接受的盐，以及其制备方法和药用用途。原生物碱类季铵盐的衍生物或其生理上可接受的盐显示出抑制溃疡性结肠炎的活性，并可用于制备相应药物。
• [EN] QUINOLINE COMPOUNDS AS INHIBITORS OF TAM AND MET KINASES<br/>[FR] COMPOSÉS DE QUINOLÉINE UTILISÉS EN TANT QU'INHIBITEURS DE KINASES TAM ET MET
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2020141470A1

  公开（公告）日：2020-07-09

  Provided herein are compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein X1, X2, X3, R1, R2, R3, R4, R5, R6 and R7 are as defined herein, which are inhibitors of one or more TAM kinases and/or c-Met kinase, and are useful in the treatment and prevention of diseases which can be treated with a TAM kinase inhibitor and/or a c-Met kinase inhibitor.

  本文提供的是Formula (I)的化合物或其药用盐，其中X1、X2、X3、R1、R2、R3、R4、R5、R6和R7的定义如本文所述，这些化合物是一种或多种TAM激酶和/或c-Met激酶的抑制剂，可用于治疗和预防可以用TAM激酶抑制剂和/或c-Met激酶抑制剂治疗的疾病。
• Facile synthesis of tetrahydroprotoberberine and protoberberine alkaloids from protopines and study on their antibacterial activities
  作者：Pi Cheng、Bin Wang、Xiubin Liu、Wei Liu、Weisong Kang、Jie Zhou、Jianguo Zeng

  DOI：10.1080/14786419.2013.867344

  日期：2014.4.3

  A series of isoquinoline alkaloids including tetrahydroprotoberberines, N-methyl tetrahydroprotoberberines and protoberberines were facile synthesised with protopines as the starting material. All compounds were evaluated for their antibacterial activities against four pathogenic bacteria Escherichia coli, Staphyloccocus aureus, Staphylococcus gallinarum and Salmonella choleraesuis. Experimental results

  以protopines为起始原料，容易合成包括四氢小pro碱，N-甲基四氢小ber碱和小ine碱在内的一系列异喹啉生物碱。评价了所有化合物对四种病原菌大肠杆菌，金黄色葡萄球菌，鸡葡萄球菌和霍乱沙门氏菌的抗菌活性。实验结果表明，原小ber碱是被测生物碱中对靶细菌活性最高的化合物。有人提出，具有较高芳香化水平的平面分子（例如黄连5和小ber碱6））或分子的正电荷（例如N-甲基四氢小pro碱11和12）对抗菌作用具有积极影响。