维生素D2 | 50-14-6

• 物质功能分类: 原料药 - 维生素类与矿物质类药 - 维生素AD类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 维生素D2
• 中文别名: 维生素丁2；alpha-骨化醇；钙化醇；麦角钙化醇；麦角钙化甾醇；麦角骨化醇
• 英文名称: Calciferol
• 英文别名: vitamin D2；ergocalciferol；vitamin D；Vit D₂；(1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5R)-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol
• CAS: 50-14-6
• 化学式: C₂₈H₄₄O
• 分子量: 396.657
• InChiKey: MECHNRXZTMCUDQ-RKHKHRCZSA-N

物化性质

• 熔点：
  114-118 °C(lit.)
• 比旋光度：
  82 º (c=3, in acetone 25 ºC)
• 沸点：
  460.3°C (rough estimate)
• 密度：
  0.9784 (rough estimate)
• 闪点：
  14 °C
• 溶解度：
  在水中的溶解度200 mg/mL,清澈至浑浊
• LogP：
  10.440 (est)
• 物理描述：
  Ergocalciferol appears as odorless white crystals. Used as a dietary supplement and food additive. (EPA, 1998)
• 颜色/状态：
  Prisms from acetone
• 气味：
  Odorless
• 味道：
  Medications associated with a metallic or bitter taste include ... vitamin D.
• 稳定性/保质期：
  Deterioration of pure crystal is negligible after storage of /9 mo/ in amber evacuated ampuls at refrigerator temperature. /Vitamin D3/
• 旋光度：
  Specific optical rotation: +82.6 @ 25 °C/D (c= 3 in acetone); +102.5 @ 20 °C/D (alcohol); specific optical rotation: +52 @ 20 °C/D (chloroform); UV max absorption (hexane): 264.5 nm (e= 458.9 +/- 7.5, 1%, 1 cm)
• 碰撞截面：
  202.4 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  20.2
• 氢给体数：
  1
• 氢受体数：
  1

ADMET

代谢

麦角钙化醇是无效的，因此，体内的第一步是通过CYP2R1的作用将此母化合物转化为25-羟基维生素D，然后产生主要循环代谢物，1,25-二羟基维生素D或钙三醇。这种主要代谢物的生成受CYP27B1的活性控制，CYP27B1是一种关键的1-羟化酶，而CYP24A1负责25-羟基化。作为次要代谢的一部分，麦角钙化醇通过D-25-羟化酶和CYP2R1的活性在肝脏中转化为25-羟基维生素D。此外，24(R),25-二羟基维生素D的形成主要在肾脏中通过25-(OH)D-1-羟化酶和25-(OH)D-24-羟化酶的作用完成。此外，还有报道称在麦角钙化醇的代谢中3-表异构酶具有显著活性，它将C3位置的羟基从α位改变为β位。形成的表异构体似乎对维生素D血浆蛋白和维生素D受体的亲和力降低。已经报道了一种替代激活代谢途径，该过程以CYP11A1的活性和其C-20的羟基化为特征。这种20-羟基化维生素D似乎具有与钙三醇相似的生物活性。

Ergocalciferol is inactive and hence, the first step in the body is ruled by the conversion of this parent compound to 25-hydroxyvitamin D by the action of CYP2R1 followed by the generation of the major circulating metabolite, 1,25-dihydroxyvitamin D or calcitrol. The generation of this major metabolite is ruled by the activity of CYP27B1 which is a key 1-hydroxylase and CYP24A1 which is responsible for the 25-hydroxylation. As part of the minor metabolism, ergocalciferol is transformed into 25-hydroxyvitamin D in the liver by the activity of D-25-hydroxylase and CYP2R1. As well, the formation of 24(R),25dihydroxyvitamin D is performed mainly in the kidneys by the action of 25-(OH)D-1-hydroxylase and 25-(OH)D-24-hydroxylase. Additionally, there are reports indicating significant activity of 3-epimerase in the metabolism of ergocalciferol which modifies the hydroxy group in C3 from the alpha position to a beta. The epimers formed seemed to have a reduced affinity for the vitamin D plasma proteins and to the vitamin D receptor. An alternative activation metabolic pathway has been reported and this process is characterized by the activity of CYP11A1 and its hydroxylation in the C-20. This 20-hydroxylated vitamin D seems to have similar biological activity than calcitriol.

来源:DrugBank

代谢

维生素D在第25位在肝脏被羟基化，生成25-羟基维生素D3，这是在血浆中循环的主要代谢物。该代谢物在肾脏进一步被羟基化为1,25-二羟基维生素D3，这是在启动肠道钙和磷酸盐的运输以及从骨骼动员矿物质方面最活跃的代谢物。

Vitamin D ... is hydroxylated at the 25 position in liver to produce 25-hydroxy-vitamin D3 which is the major metabolite circulating in the plasma. The metabolite is further hydroxylated in the kidney to 1,25-dihydroxy-vitamin D3, the most active metabolite in initiating intestinal transport of calcium & phosphate & mobilization of mineral from bone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一个极性的、生物活性代谢物，来自维生素D2的25-羟基麦角钙化醇，在大鼠治疗佝偻病方面活性约高出1.5倍，已经从猪血浆中分离出来。

A polar, biologically active metabolite of vitamin D2, 25-hydroxyergocalciferol, which is about 1.5 times more active in curing rickets in rats, has been isolated from pig plasma.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Dihydrotachysterol 是一种维生素 D 类似物，可以被认为是维生素 D2 的还原产物……在抗佝偻病活性测试中，Dihydrotachysterol 的活性大约是维生素 D 的 1/450，但在高剂量下，它在动员骨矿物质方面比维生素 D 更有效。

Dihydrotachysterol is a vitamin D analog that may be regaurded as a reduction product of vitamin D2 ... Dihydrotachysterol is about 1/450 as active as vitamin D in the antirachitic assay, but at high doses it is much more effective than vitamin D in mobilizing bone mineral.

来源:Hazardous Substances Data Bank (HSDB)

代谢

维生素D2已知的人类代谢物包括维生素D2 3-葡萄糖苷酸。

Vitamin D2 has known human metabolites that include Vitamin D2 3-glucuronide.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

维生素D2是维生素D的最常见形式，通常被添加到食品和营养补充剂中。维生素D2必须通过肝脏或肾脏转化为两种活性形式之一。一旦转化，它就会与维生素D受体结合，然后发挥多种调节作用。维生素D在维持钙平衡和调节甲状旁腺激素（PTH）方面起着重要作用。它促进肾脏对钙的重吸收，增加肠道对钙和磷的吸收，并增加骨骼中钙和磷向血浆的动员。维生素D2及其类似物似乎通过绑定到肠粘膜细胞质中的特定受体来促进钙的肠道吸收。随后，钙通过形成钙结合蛋白被吸收。激活的麦角钙化醇通过增加肠道对钙和磷的吸收来提高血清钙和磷酸盐浓度，主要是通过绑定到肠粘膜细胞质中的特定受体。随后，钙通过形成钙结合蛋白被吸收。25-羟基麦角钙化醇是麦角钙化醇的中介代谢物。尽管这种代谢物在治疗佝偻病和诱导动物吸收钙和从骨骼动员钙（入血）方面的活性比未激活的麦角钙化醇高2-5倍，但增加的活性仍然不足以在生理浓度下影响这些功能。激活的麦角钙化醇刺激骨骼的再吸收，并且对于骨骼的正常矿化是必需的。生理剂量的麦角钙化醇还促进肾脏对钙的重吸收，但这种效果的重要性尚不清楚。

Vitamin D2 is the form of vitamin D most commonly added to foods and nutritional supplements. Vitamin D2 must be transformed (hydroxylated) into one of two active forms via the liver or kidney. Once transformed, it binds to the vitamin D receptor that then leads to a variety of regulatory roles. Vitamin D plays an important role in maintaining calcium balance and in the regulation of parathyroid hormone (PTH). It promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium and phosphorus mobilization from bone to plasma. Vitamin D2 and its analogs appear to promote intestinal absorption of calcium through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. Activated ergocalciferol increases serum calcium and phosphate concentrations, primarily by increasing intestinal absorption of calcium and phosphate through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. 25-hydroxyergocalciferol is the intermediary metabolite of ergocalciferol. Although this metabolite exhibits 2-5 times more activity than unactivated ergocalciferol in curing rickets and inducing calcium absorption and mobilization (from bone) in animals, this increased activity is still insufficient to affect these functions at physiologic concentrations. Activated ergocalciferol stimulate resorption of bone and are required for normal mineralization of bone. Physiological doses of ergocalciferol also promotes calcium reabsorption by the kidneys, but the significance of this effect is not known.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：骨化醇

Compound:ergocalciferol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

维生素D2在小肠被吸收，并通过乳糜微粒运输到肝脏。除非存在与脂肪吸收不良相关的条件，否则其肠道吸收没有限制。然而，为了吸收发生，需要胆汁的存在。

Ergocalciferol is absorbed in the intestine and carried to the liver in chylomicrons. Its intestinal absorption does not present limitations unless the presence of conditions related to fat malabsorption. However, for absorption to take place, the presence of bile is required.

来源:DrugBank

吸收、分配和排泄

• 消除途径

麦角钙化醇的活性形式，钙三醇，在储存组织中不能长期保持，尤其是在饮食或UVB剥夺期间。因此，麦角钙化醇及其代谢物通过胆汁排出，肾消除的贡献较小。这种主要的粪便排出是由于维生素D代谢物与维生素D结合蛋白结合，通过cubilin-megalin受体系统介导的肾重吸收。

The active form of ergocalciferol, calcitrol, cannot be maintained for long periods in storage tissue mainly in periods of dietary or UVB deprivation. Therefore, ergocalciferol and its metabolites are excreted via the bile with a minor contribution of renal elimination. This major fecal elimination is explained due to the cubilin-megalin receptor system-mediated renal reuptake of vitamin D metabolites bound to vitamin D binding protein.

来源:DrugBank

吸收、分配和排泄

• 分布容积

循环的麦角钙化醇非常有限，因为这种化合物会迅速储存在脂肪组织中，如脂肪组织、肝脏和肌肉。这在报告中非常明显，表明肥胖患者的循环麦角钙化醇显著减少。

The amount of circulating ergocalciferol is very limited as this compound is rapidly stored in fat tissue such as adipose tissue, liver and muscle. This is very obvious in reports that indicate that circulating ergocalciferol is significantly reduced in obese patients.

来源:DrugBank

吸收、分配和排泄

• 清除

关于骨化二醇的清除率没有正式的报告。由于结构相似性，建议参考[胆钙化醇]的该参数。另一方面，建议的钙三醇的肾清除率为31毫升/分钟。

There are no formal reports regarding the clearance rate of ergocalciferol. Due to the structural similarity, it is recommended to consult this parameter with [cholecalciferol]. On the other hand, the proposed renal clearance of calcitriol is of 31 ml/min.

来源:DrugBank

吸收、分配和排泄

维生素D2和维生素D3都从小肠吸收，尽管维生素D3的吸收可能更有效。维生素D吸收最有效的肠道部位反映了维生素溶解的载体。大部分维生素首先出现在淋巴的乳糜微粒中。

Both vitamin D2 & vitamin D3 are absorbed from the small intestine, although vitamin D3 may be absorbed more efficiently. The exact portion of the gut that is most effective in vitamin D absorption reflects the vehicle in which the vitamin is dissolved. Most of the vitamin appears first within chylomicrons in lymph.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险等级：
  6.1(a)
• 危险品标志：
  T+
• 安全说明：
  S26,S28,S28A,S36,S36/37,S45
• 危险类别码：
  R26,R48/25,R24/25
• WGK Germany：
  3
• 海关编码：
  29362900
• 危险品运输编号：
  UN 2811 6.1/PG 2
• RTECS号：
  KE1050000
• 包装等级：
  II
• 危险类别：
  6.1(a)
• 危险标志：
  GHS06,GHS08
• 危险性描述：
  H301 + H311,H330,H372
• 危险性防范说明：
  P260,P280,P302 + P352 + P312,P304 + P340 + P310,P403 + P233

制备方法与用途

根据您提供的信息,维生素D2（麦角钙化醇）主要用于以下方面:

1. 预防和治疗小儿佝偻病及成人骨质软化症

2. 保持钙和磷的代谢正常,促进机体对钙和磷的吸收

3. 营养强化食品:

• 人造奶油:最大使用量为125~156μg/kg
• 乳制品:63~125μg/kg
• 婴幼儿食品:50~100μg/kg
• 乳及乳饮料:10~40μg/kg
• 固体饮料和冰淇淋:10~20μg/kg

4. 化学性质:

• 白色针状结晶或结晶性粉末,无臭无味
• 易溶于乙醇、乙醚等有机溶剂
• 遇氧或光照活性降低

5. 生产方法:

• 从植物油或酵母中提取麦角钙醇,再用紫外线照射转化而成
• 紫外线照射麦角甾醇开环得到维生素D2粗品,再精制得成品

6. 化学结构特征:

• 麦角甾醇经紫外光照射在9,10位键断裂生成维生素D2
• 分子中含有共轭双键,在265nm波长处有最大吸收

综上所述,维生素D2是一种重要的脂溶性维生素,具有促进钙磷代谢、防治佝偻病和骨质软化等作用。

反应信息

• 作为反应物：
  描述：

  维生素D2 在 咪唑 、 potassium permanganate 、 正丁基锂 、 四丁基氟化铵 、 双氧水 、 lead(IV) tetraacetate 、 sodium carbonate 、 苯基锂 、 红铝 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 苯 为溶剂， 反应 34.58h， 生成 tert-butyl(((1S,Z)-3-((E)-2-((1S,7aS)-1-((S)-2-(ethoxymethoxy)-6-methylheptan-2-yl)-7a-methylhexahydro-1H-inden-4(2H)-ylidene)ethylidene)-4-methylenecyclohexyl)oxy)dimethylsilane
  参考文献：
  名称：

  Total synthesis of biologically active 20S-hydroxyvitamin D3

  摘要：

  A total synthetic strategy of 20S-hydroxyvitamin D3 [20S-(OH)D3] involving modified synthesis of key intermediates 7 and 12, Grignard reaction to stereoselectively generate 20S-OH and Wittig-Horner coupling to establish D3 framework, was completed in 16 steps with an overall yield of 0.4%. The synthetic 20S-(OH)D3 activated vitamin D receptor (VDR) and initiated the expression of downstream genes. In addition, 20S-(OH)D3 showed similar inhibitory potency as calcitriol [1,25(OH)(2)D3] on proliferation of melanoma cells. (C) 2015 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2015.09.009
• 作为产物：
  描述：

  光甾醇 在 乙醚 作用下， 生成 维生素D2
  参考文献：
  名称：

  Windaus; Dithmar; Fernholz, Justus Liebigs Annalen der Chemie, 1932, vol. 493, p. 259,267

  摘要：

  DOI：

文献信息

• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• [EN] MICROBIOCIDAL OXADIAZOLE DERIVATIVES<br/>[FR] DÉRIVÉS D'OXADIAZOLE MICROBIOCIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2017157962A1

  公开（公告）日：2017-09-21

  Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially fungicides.

  式(I)的化合物，其中取代基如权利要求1所定义，作为杀虫剂特别是杀菌剂有用。
• [EN] INSECTICIDAL TRIAZINONE DERIVATIVES<br/>[FR] DÉRIVÉS DE TRIAZINONE INSECTICIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2013079350A1

  公开（公告）日：2013-06-06

  Compounds of the formula (I) or (I'), wherein the substituents are as defined in claim 1, are useful as pesticides.

  式(I)或(I')的化合物，其中取代基如权利要求1所定义的那样，可用作杀虫剂。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。

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