[6R,S]-folinic acid | 73951-54-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [6R,S]-folinic acid
• 英文别名: leucovorin；LCV；(6R,S)-5-formyl-5,6,7,8-tetrahydrofolate；[6R,S]-5-formyltetrahydrofolate；(6R)-Folinic acid；(2S)-2-[[4-[[(6R)-2-amino-5-formyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid
• CAS: 73951-54-9
• 化学式: C₂₀H₂₃N₇O₇
• 分子量: 473.445
• InChiKey: VVIAGPKUTFNRDU-OLZOCXBDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  216
• 氢给体数：
  7
• 氢受体数：
  10

ADMET

代谢

活体中，亚叶酸钙迅速并广泛地转化为其他四氢叶酸衍生物，包括5-甲基四氢叶酸，这是体内叶酸的主要运输和储存形式。/亚叶酸钙/

In vivo, leucovorin calcium is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body. /Leucovorin calcium/

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏和肠道粘膜主要转换为5-甲基四氢叶酸（活性）。口服给药后，亚叶酸钙的代谢非常广泛（大于90%）且迅速（在30分钟内）。而静脉给药后代谢较少（约66%），肌肉注射给药后代谢约为72%，且代谢速度较慢。

Hepatic and intestinal mucosal, mainly to 5-methyltetrahydrofolate (active). After oral administration, leucovorin is substantially (greater than 90%) and rapidly (within 30 minutes) metabolized. Metabolism is less extensive (about 66% after intravenous and 72% after intramuscular administration) and slower with parenteral administration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

既不正常的叶酸摄入量也没有过高的叶酸摄入量与肝脏损伤或肝脏测试异常有关。在长期临床试验中，与安慰剂相比，使用叶酸治疗时血清酶和胆红素升高的频率并没有增加。高剂量叶酸（每日达15毫克）的使用并未与明显的副作用、ALT升高或肝毒性有关联。

Neither normal nor excessively high intakes of folate are associated with liver injury or liver test abnormalities. In long term clinical trials, serum enzyme and bilirubin elevations were no more frequent with folic acid therapy than with placebo. Use of high doses of folic acid (up to 15 mg daily) has not been associated with appreciable adverse reactions, ALT elevations or hepatotoxicity.

来源:LiverTox

毒理性

• 相互作用

甲酰四氢叶酸与氟尿嘧啶同时使用可能会增加氟尿嘧啶的治疗效果和毒性；尽管这两种药物可以一起使用以获得治疗优势，但需要谨慎。

Concurrent use of leucovorin /with fluorouracil/ may increase the therapeutic and toxic effects of fluorouracil; although the two medications may be used together for therapeutic advantage, caution is necessary.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

将肿瘤细胞暴露于还原型叶酸（如亚叶酸钙）与氟嘧啶类药物（如5-氟尿嘧啶或5-氟-2'脱氧尿嘧啶）共同使用，可以显著提高这些药物的活性。现有证据表明，这种协同作用的机制是通过对胸苷酸合成酶与氟脱氧尿苷酸之间形成的复合物进行动力学稳定化，并且涉及到胸苷酸合成酶反应的辅因子，即5,10-亚甲基四氢叶酸。这种效应导致胸苷酸核苷酸的耗尽时间延长，从而增加了细胞死亡的水平。

Exposure of tumor cells to reduced folates /like leucovorin/ before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

大量甲酰四氢叶酸可能会对抗这些药物的抗惊厥作用：/巴比妥类抗惊厥药、乙内酰脲类抗惊厥药、普里米酮/。

Large dose of leucovorin may counteract the anticonvulsant effects of these medications: /barbiturate anticonvulsants, hydantoin anticonvulsants, primidone/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

斯普拉格道莱大鼠被用来展示一氧化二氮的效应，以及在使用叶酸预处理的情况下的效应，这些效应涉及到生殖指标和胎儿发育。... 在怀孕的第9天，将动物分组暴露于70-75%的一氧化二氮，有的在暴露前12小时以及暴露前立即接受了0.1毫克叶酸的腹腔注射。随后将这些胎儿的发育情况与各种对照组进行比较。胎儿的存活率没有显著差异，但是接触一氧化二氮的两个组别的胎儿体重都有所减轻。在骨骼成熟指标中，只有未接受叶酸的一氧化二氮组的 ossified sternebrae 数量减少了。未经处理的一氧化二氮组的大骨骼异常发生率显著增加，是对照组的五倍，而接受叶酸的一氧化二氮组的大骨骼异常发生率与对照组没有显著差异。因此，可以得出结论，叶酸预处理至少可以在一定程度上减轻大鼠一氧化二氮的致畸效应。

The Sprague Dawley rat was used to demonstrate the effect of nitrous oxide, with and without folinic pretreatment, on reproductive indices and fetal development. ... Groups of animals were exposed to 70-75% nitrous oxide on day 9 of pregnancy with or without folinic acid 0.1 mg ip 12 hr before, and immediately before, exposure. Subsequent fetal development was compared with that of various control groups. There were no significant differences in fetal survival, but fetal wt were reduced in both groups exposed to nitrous oxide. Of the indices of skeletal maturity, the number of ossified sternebrae was reduced only in the nitrous oxide group not receiving folinic acid. The incidence of major skeletal abnormalities in the untreated nitrous oxide group was significantly increased to five times that of the control groups, whereas the incidence in the nitrous oxide group receiving folinic acid was not significantly different from control. It is concluded that pretreatment with folinic acid can at least partially reduce the teratogenic effects of nitrous oxide in the rat.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作用持续时间：所有给药途径：3到6小时。

Duration of action: All routes: 3 to 6 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作用开始时间：口服：20至30分钟。肌肉注射：10至20分钟。静脉注射：少于5分钟。

Onset of action: Oral: 20 to 30 minutes. Intramuscular: 10 to 20 minutes. Intravenous: Less than 5 minutes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

中等量地穿过血脑屏障；主要集中在大脑和肝脏。

Crosses blood-brain barrier in moderate amounts; largely concentrated in liver.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：肾脏：80-90%。粪便：5-8%。

Elimination: Renal: 80-90%. Fecal: 5-8%.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

亮氨酸是一种以叶酸为前体的化合物。

反应信息

• 作为产物：
  描述：

  folate 在 sodium hydroxide 、 sodium tetrahydroborate 、 sodium dithionite 、 维生素 C 作用下， 以 吡啶 、 水 、 二甲基亚砜 为溶剂， 反应 90.0h， 生成 [6R,S]-folinic acid
  参考文献：
  名称：

  ÜberPterinchemie 76. Mitteilung [1] Eine einfache合成von Leucovorin †

  摘要：

  叶绿素的便捷合成

  DOI：

  10.1002/hlca.19800630850

文献信息

• A simple and effective method for preparation of the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin)
  作者：Lilias Rees、Colin J. Suckling、Hamish C. S. Wood

  DOI：10.1039/c39870000470

  日期：——

  Acylation of 6(RS)-tetrahydrofolate with (–)-menthyl chloroformate afforded an N-5 derivative which was separable into its diastereoisomers by extraction with n-butanol; these derivatives were converted separately into the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate by treatment with a mixture of formic acid and hydrogen bromide in acetic acid followed by hydrolysis.

  用（-）-薄荷基氯甲酸酯酰化6（RS）-四氢叶酸，得到N-5衍生物，可通过用正丁醇萃取将其分离成非对映异构体。通过用甲酸和溴化氢在乙酸中的混合物处理，然后水解，将这些衍生物分别转化为5-甲酰基四氢叶酸酯的6（R）-和6（S）-非对映异构体。
• Enantioselektive Katalysen, 135. Mitt. [1]. Stereoselektive Hydrierung von Folsaüure und2-Methylchinoxalin mit optisch aktiven Rhodium(I)-Phosphan-Komplexen
  作者：Henri Brunner、Sabine Rosenboem

  DOI：10.1007/s007060070017

  日期：2000.12.13

   In the hydrogenation of the C*N double bonds of the pyrazine ring of folic acid to 5,6,7,8-tetrahydrofolic acid a new asymmetric center is formed at C6 of the pteridine system. With rhodium(I) catalysts made from optically active phosphanes, which are immobilized on silical gel, the hydrogenation in aqueous solution can be controlled stereoselectively. The highest diastereomeric excess of ca . 40%

   在叶酸的吡嗪环的C * N双键氢化为5,6,7,8-四氢叶酸的过程中，在蝶啶系统的C6处形成新的不对称中心。使用固定在硅胶上的由旋光性膦制成的铑（I）催化剂，可以选择性地控制水溶液中的氢化。 ca 的最高非对映异构体过量 。（-）- BPPM 获得40％ 含有催化剂。还可以用铑（I）-膦催化剂均匀地在水溶液中氢化生物分子叶酸，其配体包含磺酸基和聚醚片段。与非均相催化剂相比，均相氢化进行得较慢并且非对映选择性有所降低。2-甲基喹喔啉的氢化是还原叶酸的模型系统。普通的铑（I）-膦催化剂仅提供小的对映选择性。
• Compositions and methods for regulation of gene expression with, and detection of, folinic acid and folates
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US10450573B2

  公开（公告）日：2019-10-22

  Aptamers that specifically bind to ligands of folinic acid, a folate, and derivatives thereof (which may be referred to herein as ligands) are provided, and compositions and methods of use thereof. The aptamers and switches of the invention provide biological sensing capability for detecting the ligands, and are effective in sensing in vitro and in vivo. By specific sensing of the ligand, the aptamers of the invention provide a means of engineering an inducible gene regulatory system that enables dose-dependent control over gene expression in response to the ligand, in vivo and in vitro.

  本发明提供了与亚叶酸配体、叶酸及其衍生物（在此可称为配体）特异性结合的适配体，以及其组合物和使用方法。本发明的适配体和开关具有检测配体的生物传感能力，并能在体外和体内有效传感。通过对配体的特异性传感，本发明的适配体提供了一种可诱导基因调控系统的工程设计方法，该系统可针对配体在体内和体外对基因表达进行剂量依赖性控制。
• COMPOSITIONS AND METHODS FOR REGULATION OF GENE EXPRESSION WITH, AND DETECTION OF, FOLINIC ACID AND FOLATES
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US20200255835A1

  公开（公告）日：2020-08-13

  Aptamers that specifically bind to ligands of folinic acid, a folate, and derivatives thereof (which may be referred to herein as ligands) are provided, and compositions and methods of use thereof. The aptamers and switches of the invention provide biological sensing capability for detecting the ligands, and are effective in sensing in vitro and in vivo. By specific sensing of the ligand, the aptamers of the invention provide a means of engineering an inducible gene regulatory system that enables dose-dependent control over gene expression in response to the ligand, in vivo and in vitro.
• Über Pterinchemie 76. Mitteilung [1] Eine einfache Synthese von Leucovorin
  作者：Esam Khalifa、Abhoy N. Ganguly、Jost H. Bieri、Max Viscontini

  DOI：10.1002/hlca.19800630850

  日期：1980.12.10

  A Convenient Synthesis of Leucovorin

  叶绿素的便捷合成