倒千里光碱 | 480-54-6

• 物质功能分类: 分析化学 - 标准品 - 食品和化妆品标准品
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 中文名称: 倒千里光碱
• 英文名称: retrorsine
• 英文别名: beta-Longilobine；retorsine；RTS；12,18-dihydroxy-senecionane-11,16-dione；β-longilobine；(1R,4Z,6R,7S,17R)-4-ethylidene-7-hydroxy-7-(hydroxymethyl)-6-methyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione
• CAS: 480-54-6
• 化学式: C₁₈H₂₅NO₆
• 分子量: 351.4
• InChiKey: BCJMNZRQJAVDLD-CQRYIUNCSA-N

物化性质

• 熔点：
  208-211 °C (lit.)
• 比旋光度：
  D18 -17.6° (c = 1.99 in ethanol)
• 沸点：
  485.2°C (rough estimate)
• 密度：
  1.32±0.1 g/cm3 (20 ºC 760 Torr)
• 颜色/状态：
  Colorless prisms
• 溶解度：
  In water, 3.08X10+4 mg/L @ 25 °C /Estimated/
• 蒸汽压力：
  1.9X10-14 mm Hg @ 25 °C /Estimated/
• 稳定性/保质期：
  Stability: stable at room temperature in closed containers: best stored under nitrogen -15 °C.
• 旋光度：
  Max absorption (water): 217 nm (epsilon= 201, 1%, 1 cm); specific optical rotation (chloroform): -61.4 deg @ 20 °C/D
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
• 解离常数：
  pKa = 6.01 /Estimated/
• 保留指数：
  2585
• LogP：
  log Kow = -1.88 @ 25 °C /Estimated/

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  96.3
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

使用 retrorsine 的研究表明，大鼠肝脏微粒体混合功能氧化酶系统形成了 N-氧化物和吡咯代谢物/retrorsine 吡咯/。

Studies with retrorsine have confirmed the formation of the n-oxide and pyrrolic metabolites /retrorsine pyrrole/ by the mixed-function oxidase system of the microsomal fraction of rat liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在动物中，吡咯烷生物碱的主要代谢途径是：(a) 酯基的水解；(b) N-氧化；和(c) 吡咯烷环的脱氢生成吡咯衍生物。途径(a)和(b)被认为是解毒机制。途径(c)导致有毒代谢物。途径(a)发生在肝脏和血液中；途径(b)和(c)是通过微粒体混合功能氧化酶系统在肝脏中产生的。/吡咯烷生物碱/

In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N-oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives. Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在体内，从吡咯里西啶生物碱（PAs）中的倒千里光碱（RET）和倒千里光碱-N-氧化物（RET-NO）的尿液代谢物的研究已经在大鼠中进行。异色酸（INA）、吡咯代谢物、N-氧化物和倒千里光宁分别占给药RET的31.0%、10.3%、10.8%和0.39%。预先给予三正丙基磷酸酯（TOCP）的大鼠对吡咯代谢物和INA的排泄没有影响。苯巴比妥（PB）增加了吡咯代谢物和INA的排泄，相应地减少了RET和N-氧化物的排泄；倒千里光宁的水平保持不变。当RET-NO通过腹腔注射给药时，与RET处理的相比，尿液中的吡咯代谢物、INA和RET的水平降低。RET-NO口服给药产生了显著更高水平的吡咯代谢物、INA和RET。这些结果表明，酯酶水解在INA的形成中扮演次要角色，并且吡咯代谢物与INA形成之间可能存在共同的代谢途径。

The in vivo metabolism and excretion of the urinary metabolites from the pyrrolizidine alkaloids (PAs), retrorsine (RET) and retrorsine-N-oxide (RET-NO) have been studied in rats. Isatinecic acid (INA), pyrrolic metabolites, N-oxides and retronecine accounted for 31.0, 10.3, 10.8 and 0.39% of the administered RET. Predosing rats with triorthocresyl phosphate (TOCP), had no effect on the excretion of pyrrolic metabolites and INA. Phenobarbital (PB) increased the excretion of both pyrrolic metabolites and INA with a corresponding decrease in the excretion of RET and N-oxides; the retronecin levels remained unaltered. When RET-NO was administered i.p., the urinary levels of pyrrolic metabolites, INA and RET were decreased relative to those treated with RET. The p.o. administration of RET-NO produced significantly higher levels of pyrrolic metabolites, INA and RET. These results suggest that esterase hydrolysis plays a minor role in the formation of INA and that a common metabolic pathway may exist between pyrrolic metabolites and INA formation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

...将逆回素给药于一组年轻的成年雄性大鼠，并检查了广泛研究的肝脏CYP异构体跨越四个家族以及关键酶CYP还原酶的mRNA和蛋白的诱导或增强表达。与未经处理的对照组大鼠相比，逆回素处理的大鼠肝脏微粒体中正常表达的CYPs 1A2、2B1/2和2E1的蛋白水平显著增加（P<0.05），但CYP 4A3、CYP 3A1和CYP还原酶的蛋白水平在逆回素处理后没有变化。此外，在对照组大鼠肝脏中无法检测到的CYP 1A1的mRNA和蛋白在逆回素暴露后被诱导。目前的研究结果表明，在大鼠中，逆回素暴露增强了或诱导了肝脏CYPs 1A1、1A2、2E1和2B1/2的表达，提示这些酶中的一个或多个可能参与逆回素的代谢。

...Retrorsine was administered to a cohort of young adult male rats and examined induction or enhanced expression of mRNA and protein for widely studied hepatic CYP isoforms spanning four families together with the essential enzyme CYP reductase. The protein levels of normally expressed CYPs 1A2, 2B1/2, and 2E1 increase significantly in rat liver microsomes from retrorsine-treated rats compared to untreated control rats (P< 0.05), but protein levels of CYP 4A3, CYP 3A1, and CYP reductase were unchanged after retrorsine treatment. In addition, CYP 1A1 mRNA and protein, which are not detectable in the livers of control rats, were induced after retrorsine exposure. The results of the present study demonstrate enhanced or induced expression of hepatic CYPs 1A1, 1A2, 2E1, and 2B1/2 in response to retrorsine exposure in rats, suggesting that one or more of these enzymes may be involved in retrorsine metabolism.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

没有关于人类的数据。动物致癌性的证据有限。总体评估：第3组：该物质对人类致癌性无法分类。

No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.

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剂：雷斯托辛

IARC Carcinogenic Agent:Retrorsine

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：第3组：无法归类其对人类致癌性

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity 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著：第10卷：（1976年）一些天然存在的物质

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

来源:International Agency for Research on Cancer (IARC)

毒理性

• 相互作用

...对Porton Wistar大鼠幼崽通过胃管单次给予30毫克/千克体重的 retrorsine，给药后100天接受全身400拉德辐射，共31只大鼠...在25只幸存者中，有5个肝母细胞瘤，5个乳腺肿瘤，2个肾细胞癌和1个肝细胞癌伴肺转移，1个肺癌，1个结肠癌，1个脾血管内皮瘤，1个肱骨骨肉瘤，1个白血病和1个颈部梭形细胞肿瘤的案例... /没有对照组出现/

...Weanling Porton Wistar rats were given single doses of 30 mg/kg body weight retrorsine by stomach tube...with whole-body irradiation of 400 rads 100 days after dosing, in 31 rats... In 25 survivors, there were 5 hepatomas, 5 mammary tumors, 2 renal carcinomas and 1 case each of carcinoma of the liver with pulmonary metastases, carcinoma of the lung, carcinoma of the colon, hemangioendothelioma of the spleen, osteosarcoma of the humerus, leukemia and spindle-cell tumor of the neck... /no controls presented/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物研究中，最高浓度被发现于肝脏、肺、肾脏和脾脏。/吡咯烷生物碱/

In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当向大鼠腹腔注射吡咯烷生物碱、反式 retrorsine 60 mg/kg、反式 retrorsine N-氧化物 60 mg/kg 时，24小时内，剂量的0.2-12.4% 以代谢吡咯的形式随尿液排出。生物碱的肝毒性与其在体内产生的吡咯数量之间存在大致的相关性。当大鼠口服或腹腔注射反式 retrorsine 50 mg/kg 并在给药后不同时间点处死时，代谢吡咯被发现强烈结合在肝脏上，并且在形成后48小时或更长时间内，在一定程度上也结合在肺和其他器官上。

When pyrrolizidine alkaloids, retrorsine 60 mg/kg, retrorsine n-oxide 60 mg/kg were administered ip to rats, 0.2-12.4% of the doses were excreted in the urine within 24 hr as metabolic pyrroles. There was a rough correlation between the hepatotoxicity of alkaloids and the amount of pyrroles to which they gave rise to in vivo. When rats were dosed orally or ip with retrorsine 50 mg/kg and sacrificed after various times, metabolic pyrroles were found bound strongly to the liver, and to /lesser/ extent the lung and other organs, for 48 hr or more after being formed.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T
• 安全说明：
  S22,S36/37/39,S45
• 危险类别码：
  R25
• WGK Germany：
  3
• 危险品运输编号：
  UN 1544
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

生物活性

Retrorsine 是一种天然存在的有毒吡咯利西啶生物碱。Retrorsine 可以与 DNA 结合，抑制肝细胞的增殖能力。Retrorsine 可用于肝细胞损伤的研究。

体外研究

Retrorsine (60-240 μM; 24 hours) significantly reduces HSEC-CYP3A4 cells viability and GSH levels, and increases formation of pyrrole-protein adducts.

Cell Viability Assay

Cell Line:	HSEC-CYP3A4 cells
Concentration:	60 μM, 120 μM , 240 μM
Incubation Time:	24 hours
Result:	Significantly decreased cell viability.

体内研究

Retrorsine (30 mg/kg; i.p.; twice) impairs liver regeneration in the PBL model not only by an S or G2/M phase block, but also by a block located before the G1/S transition of the cell cycle.

Animal Model:	Male Wistar rats (180±20 g), portal branch ligation (PBL) model
Dosage:	30 mg/kg
Administration:	Intraperitoneal injection, twice, separated by 2-week interval
Result:	Strongly impaired the liver weight gain, protein and DNA synthesis as well as induction of cell cycle related proteins in the regenerating lobes after PBL.

反应信息

• 作为反应物：
  描述：

  倒千里光碱 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 反应 4.5h， 以72%的产率得到retronecic acid
  参考文献：
  名称：

  合成新的大环化合物。第6部分。吡啶-维甲酸，一种新的合成生物碱

  摘要：

  2，6-双（溴甲基）吡啶与天然存在的C 10烯酸（逆向烯酸）反应，导致形成新的半合成环状二酯生物碱，吡啶-维甲酸。该产品是吡咯烷核生物碱的类似物，并保留了通常认为对该类生物碱具有毒性的那些特征。对注射了逆转录酶和合成类似物的小鼠进行的生物学测试表明，其细胞毒性作用相似。

  DOI：

  10.1039/p19810000408
• 作为产物：
  描述：

  靛红定 生成 倒千里光碱
  参考文献：
  名称：

  BORSTEL, KIRSTEN V.;WITTE, LUDGER;HARTMANN, THOMAS, PHYTOCHEMISTRY, 28,(1989) N, C. 1635-1638

  摘要：

  DOI：

文献信息

• Novel triterpene derivatives
  申请人：onepharm Research & Development GmbH

  公开号：EP2228380A1

  公开（公告）日：2010-09-15

  The present invention encompasses novel triterpene compounds of general formula I wherein R3a R3b R11a R11b R31 and R32 are defined as in claim 1, which are suitable for the prevention and/or treatment of diseases mediated by 11β-HSD and the use thereof for preparing a medicament having the above-mentioned properties.

  本发明涵盖了一般式I的新型三萜化合物， 其中 R3a、R3b、R11a、R11b、R31和R32如权利要求1所定义，适用于预防和/或治疗由11β-HSD介导的疾病，并用于制备具有上述特性的药物。
• [EN] NOVEL TRITERPENE DERIVATIVES<br/>[FR] NOUVEAUX DÉRIVÉS TRITERPÉNIQUES
  申请人：ONEPHARM RES & DEV GMBH

  公开号：WO2012020019A1

  公开（公告）日：2012-02-16

  The present invention encompasses compounds of general formula (I) wherein R11a to R30 and X are defined as in claim 1, which are suitable for the treatment of and/or prevention of chronic inflammatory diseases, autoimmune diseases, skin diseases, bone diseases, metabolic diseases, infectious diseases and cancer.

  本发明涵盖了一般式（I）中R11a到R30和X的化合物，其中如权利要求书中所定义的，适用于治疗和/或预防慢性炎症性疾病、自身免疫疾病、皮肤疾病、骨疾病、代谢性疾病、传染病和癌症。
• METHODS AND COMPOSITIONS FOR TREATING INFECTION
  申请人：UNIVERSITY OF ROCHESTER

  公开号：US20150238473A1

  公开（公告）日：2015-08-27

  Provided herein are compositions and methods for treating or preventing infection.

  本文提供了用于治疗或预防感染的组合物和方法。
• Some semi-synthetic derivatives of pyrrolizidine alkaloids
  作者：A. R. Mattocks

  DOI：10.1039/j39690002698

  日期：——

  Diesters (VII–XXIII) of retronecine (I), and acyl derivatives of the alkaloids indicine (XXIV), monocrotaline (XXVII), and retrorsine (XXIX), have been prepared for toxicological studies. Dichlororetronecine (III), is described, and also retronamine (V), an amino-analogue of retronecine, which provide a simple route to amide analogues of pyrrolizidine esters.

  已经准备了逆转录酶（I）的二酯（VII–XXIII），以及生物碱标记（XXIV），一丁香酚（XXVII）和逆转录酶（XXIX）的酰基衍生物进行毒理学研究。描述了二氯维甲酸（III），以及逆转录胺（V），逆转录胺的氨基类似物，其提供了简单的途径来制备吡咯并咪唑酯的酰胺类似物。
• Use of three-dimensional microfabricated tissue engineered systems for pharmacologic applications
  申请人：Vacanti P. Joseph

  公开号：US20060019326A1

  公开（公告）日：2006-01-26

  The present invention generally relates to a combination of the fields of tissue engineering, drug discovery and drug development. It more specifically provides new methods and materials for testing the efficacy and safety of experimental drugs, defining the metabolic pathways of experimental drugs and characterizing the properties (e.g., side effects, new uses) of existing drugs. Preferably, evaluation is carried out in three-dimensional tissue-engineered systems, wherein drug toxicity, metabolism, interaction and/or efficacy can be determined.

  本发明通常涉及组织工程、药物发现和药物开发领域的组合。更具体地提供了测试实验药物的功效和安全性、定义实验药物的代谢途径以及表征现有药物的属性（例如副作用、新用途）的新方法和材料。优选地，在三维组织工程系统中进行评估，可以确定药物毒性、代谢、相互作用和/或功效。