(1S,7aR)-7-[({(2S)-2,3-dihydroxy-2-[(1S)-1-methoxyethyl]-3-methylbutanoyl}oxy)methyl]-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yl (2Z)-2-methylbut-2-enoate | 303-34-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 英文名称: (1S,7aR)-7-[({(2S)-2,3-dihydroxy-2-[(1S)-1-methoxyethyl]-3-methylbutanoyl}oxy)methyl]-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yl (2Z)-2-methylbut-2-enoate
• 英文别名: [(7S,8R)-7-[(Z)-2-methylbut-2-enoyl]oxy-5,6,7,8-tetrahydro-3H-pyrrolizin-1-yl]methyl (2S)-2,3-dihydroxy-2-[(1S)-1-methoxyethyl]-3-methylbutanoate
• CAS: 303-34-4
• 化学式: C₂₁H₃₃NO₇
• 分子量: 411.5
• InChiKey: QHOZSLCIKHUPSU-PNFBIMPKSA-N

物化性质

• 熔点：
  96.5-97.0℃
• 比旋光度：
  D -4° (10% alc)
• 沸点：
  531.2°C (rough estimate)
• 密度：
  1.21±0.1 g/cm3 (20 ºC 760 Torr)
• LogP：
  1.280
• 物理描述：
  Lasiocarpine appears as colorless plates or beige crystalline solid. (NTP, 1992)
• 颜色/状态：
  COLORLESS PLATES
• 溶解度：
  less than 0.1 mg/mL at 68° F (NTP, 1992)
• 稳定性/保质期：
  DECOMP SLOWLY ON STANDING IN AIR @ ROOM TEMP
• 旋光度：
  SPECIFIC OPTICAL ROTATION: -3.0 DEG @ 16 °C/D (IN ETHANOL)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

代谢

使用毛果芸香碱的研究已经确认了由大鼠肝微粒体混合功能氧化酶系统形成的吡咯代谢物。去氢毛果芸香碱已被分离并鉴定为毛果芸香碱微粒体氧化的产物。

STUDIES WITH LASIOCARPINE HAVE CONFIRMED THE FORMATION OF PYRROLIC METABOLITES BY THE MIXED-FUNCTION OXIDASE SYSTEM OF THE MICROSOMAL FRACTION OF RAT LIVER. DEHYDROHELIOTRIDINE HAS BEEN ISOLATED & IDENTIFIED AS A PRODUCT OF MICROSOMAL OXIDATION OF LASIOCARPINE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在尿液中...在大鼠注射后16小时获得...未改变的毛果芸香碱（剂量的1-1.5%），日照飞蓬碱（1.5-3%），日照飞蓬碱N-氧化物（6%）和带有欧普因和7-天使日照飞蓬碱（预期部分水解产物）色谱性质的少量碱基。...24小时尿液样本中的代谢物...给药毛果芸香碱的8.5%。

IN URINE ... OBTAINED 16 HR AFTER INJECTION ... TO RATS ... UNCHANGED LASIOCARPINE (1-1.5% OF DOSE), HELIOTRIDINE (1.5-3%), HELIOTRIDINE N-OXIDE (6%) & TRACES OF BASES WITH CHROMATOGRAPHIC PROPERTIES OF EUROPINE & 7-ANGELYHELIOTRIDINE (EXPECTED PRODUCTS OF PARTIAL HYDROLYSIS). ... METABOLITES IN 24-HR URINE SAMPLE ... 8.5% OF ADMIN LASIOCARPINE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

人类胚胎肝脏切片将吡咯里西啶生物碱LASIOCARPINE转化为吡咯，这通过正艾尔利希显色反应得到指示，而肺组织则没有。

HUMAN EMBRYONIC LIVER SLICES CONVERTED THE PYRROLIZIDINE ALKALOID LASIOCARPINE INTO PYRROLES, AS INDICATED BY A POS EHRLICH COLOR REACTION, WHEREAS LUNG TISSUE DID NOT.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

毛果芸香碱对肝细胞有毒，但对肺细胞无毒，因为肺细胞无法将吡咯里西啶生物碱代谢为吡咯。在培养中，将毛果芸香碱应用于人肝细胞会导致DNA、RNA和蛋白质合成的抑制；细胞空泡化，阻止有丝分裂，并形成巨大细胞（“巨细胞”）。(A15431) 对肝脏的影响包括实质细胞的出血性坏死，实质细胞及其核和核仁的明显增大，纤维化或肝硬化，细胞分裂的抑制，以及可能的肿瘤形成。(A15432) 氢化可的松诱导色氨酸吡咯酶活性，在长期用毛果芸香碱处理的鼠肝中，这表明翻译机制是完整的。然而，在无明显有丝分裂活动的情况下，巨细胞对3H-胸腺嘧啶的摄取增加，这表明这些细胞正处于肥大过程中。它们可能作为肝细胞有丝分裂的长期、强效抑制剂，它们在果蝇中具有诱变性，并在白细胞中引起染色体断裂。毛果芸香碱和其他吡咯里西啶生物碱慢性中毒的一个不寻常结果是肝细胞逐渐增大，直径可达正常的三倍，伴随着核直径的相应增加。这种异常被称为巨细胞症，可能与中央静脉的轻度纤维化和胆管增殖有关。在增大的肝细胞中粗糙内质网的突出是代谢活动增加的标志。(A15433)

Lasiocarpine is toxic to liver cells but not to lung cells, which is unable to metabolize the pyrrolizidine alkaloids to pyrroles. The application of lasiocarpine to human liver cells in culture is followed by inhibition of DNA, RNA and protein synthesis; vacuolation of the cells, the prevention of mitosis and the formation of giant cells (“megalocytes”). (A15431) Effects on the liver include hemorrhagic necrosis of parenchymal cells, marked enlargement of parenchymal cells and of their nuclei and nucleoli, fibrosis or cirrhosis, depression of cell division, and possibly neoplasia. (A15432) The inducibility of tryptophan pyrrolase activity by hydrocortisone, in the livers of rats treated chronically with lasiocarpine is an indication that translational mechanisms are intact. However, the increased uptake of 3H-thymidine by megalocytes, in the absence of observable mitotic activity, suggests that these cells are in the process of hypertrophy. They may act as prolonged, potent inhibitors of mitosis in hepatocytes, they are mutagenic in Drosophila and cause chromosome breakage in leukocytes. One of the unusual results of chronic poisoning by lasiocarpine and other members of the pyrrolizidine alkaloids is progressive enlargement of liver cells to up to three times the normal diameter, with an accompanying proportionate increase in nuclear diameter. The term megalocytosis has been applied to this abnormality which may be associated with mild fibrosis of central veins and proliferation of bile ducts. The prominence of rough ER in enlarged hepatocytes is s a sign of increased metabolic activity. (A15433)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌性证据

致癌性分类：1）人类证据：不可用；2）动物证据：充分。对人类致癌风险的总体评估为2B组：该物质可能对人类致癌。/来自表格/

Classification of carcinogenicity: 1) evidence in humans: not available; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：鹰靛蓝

IARC Carcinogenic Agent:Lasiocarpine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专论集：第10卷：（1976年）一些自然存在的物质

IARC Monographs:Volume 10: (1976) Some Naturally Occurring Substances

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

LASROCARPINE（随机标记，44%在氨基醇中）通过静脉给药给大鼠（总剂量为5毫克），4小时后标记分布如下：尸体，6.4%；肠道，8.6%；睾丸，0.1%；肺，0.05%；肾脏，0.26%；心脏，0.05%；脾脏，0.01%；大脑，0.03%；尿液，27.2%；肝脏，2.8%；呼出的二氧化碳，9.3%。肝脏的进一步分离结果显示，三氯乙酸提取物中有1.73%，蛋白质中有0.6%，脂质中有0.48%，核酸中有0.005%。

LASROCARPINE (RANDOMLY LABELLED, 44% IN THE AMINO ALCOHOL) WAS ADMIN IP TO RATS (TOTAL DOSE, 5 MG) DISTRIBUTION OF LABEL AFTER 4 HR WAS AS FOLLOWS: CARCASS, 6.4%; INTESTINES, 8.6%; TESTES, 0.1%; LUNG, 0.05%; KIDNEY, 0.26%; HEART, 0.05%; SPLEEN, 0.01%; BRAIN, 0.03%; URINE, 27.2%; LIVER, 2.8%, EXPIRED CO2, 9.3% FRACTIONATION OF LIVER RESULTED IN 1.73% IN A TRICHLOROACETIC ACID EXTRACT, 0.6% IN PROTEIN, 0.48% IN LIPID & 0.005% IN NUCLEIC ACIDS.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险类别：
  6.1(b)
• 包装等级：
  III