7,12-二羟基-4-胆甾烯-3-酮 | 1254-03-1

• 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: 7,12-二羟基-4-胆甾烯-3-酮
• 英文名称: 7α,12α-dihydroxycholest-4-ene-3-one
• 英文别名: 7α,12α-dihydroxy-4-cholesten-3-one；7α,12α-dihydroxycholest-4-en-3-one；7alpha,12alpha-Dihydroxycholest-4-en-3-one；(7R,8R,9S,10R,12S,13R,14S,17R)-7,12-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one
• CAS: 1254-03-1
• 化学式: C₂₇H₄₄O₃
• 分子量: 416.645
• InChiKey: UQPYXHJTHPHOMM-NIBOIBLTSA-N

物化性质

• 熔点：
  215-218?C
• 沸点：
  549.9±50.0 °C(Predicted)
• 密度：
  1.07±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7,12-二羟基-4-胆甾烯-3-酮 、 氢(+1)阳离子 、 NADPH(4-) 生成 7alpha,12alpha-二羟基-5beta-胆甾烷-3-酮 、 NADP⁺
  参考文献：
  名称：

  Cloning and expression of cDNA of human Delta4-3-oxosteroid 5beta-reductase and substrate specificity of the expressed enzyme

  摘要：

  The enzyme Δ4‐3‐oxosteroid 5β‐reductase (3‐oxo‐5β‐steroid: NADP+ oxidoreductase and 4,5β‐dihydrocortisone: NADP+Δ4‐oxidoreductase) catalyzes the reduction of the Δ4 double bond of bile acid intermediates and steroid hormones carrying the Δ4‐3‐one structure in the A/B cis configuration. Human Δ4‐3‐oxosteroid 5β‐reductase cDNA was isolated from a liver cDNA library by cross hybridization with a previously cloned rat cDNA, which was used as a probe [Onishi, Y., Noshiro, M., Shimosato, T. & Okuda, K.‐I. (1991) FEBS Lett. 283, 215–218]. DNA sequence analysis of a hybridization‐positive clone predicted the human Δ4‐3‐oxosteroid 5β‐reductase to contain 326 amino acids. The amino acid sequence of the human Δ4‐3‐oxosteroid 5β‐reductase had 79% overall identity to the rat enzyme sequence. It also showed 54% and 50% overall identity with rat 3α‐hydroxysteroid dehydrogenase and human aldose reductase, respectively. RNA blotting analysis demonstrated the existence of a single Δ4‐3‐oxosteroid 5β‐reductase mRNA of approximately 2.7 kb in human liver. Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7α,12α‐dihydroxy‐4‐cholesten‐3‐one and 7α‐hydroxy‐4‐cholesten‐3‐one. In addition, the expressed enzyme showed a small but significant 5β‐reduction activity toward 11β,17α,21‐trihydroxy‐Δ4‐pregnene‐3,20‐dione (cortisol) and 17β‐hydroxy‐Δ4‐androsten‐3‐one (testosterone) whereas no activity was observed toward Δ4‐pregnene‐3,20‐dione (progesterone) or Δ4‐androstene‐3‐17‐dione (androstenedione). The substrate specificity of the human enzyme is considerably narrower than that of the rat enzyme, and the enzyme seems to be more important for bile acid biosynthesis than for metabolism of steroid hormones.

  DOI：

  10.1111/j.1432-1033.1994.tb19947.x
• 作为产物：
  描述：

  cholic acid 3,7,12-triacetate 在 盐酸 、 sodium hypochlorite 、 Jones reagent 、 正丁基锂 、 高氯酸 、 2,2,6,6-四甲基哌啶氧化物 、 palladium 10% on activated carbon 、 水 、 氢气 、 氯甲酸乙酯 、 三乙胺 、 三氟乙酸 、 potassium bromide 、 potassium hydroxide 、 sodium hydroxide 、 2-碘酰基苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 溶剂黄146 、 二甲基亚砜 、 乙酸乙酯 、 丙酮 为溶剂， 反应 71.75h， 生成 7,12-二羟基-4-胆甾烯-3-酮
  参考文献：
  名称：

  有效合成7alpha，12alpha-dihydroxy-4-cholesten-3-one及其生物前体7alpha-hydroxy-4-cholesten-3-one：胆汁酸生物合成中的关键中间体。

  摘要：

  本文介绍了化学合成7alpha，12alpha-dihydroxy-4-cholesten-3-one（1a）及其生物学前体7alpha-hydroxy-4-cholesten-3-one（1b）的方法。胆固醇从胆汁酸生物合成的主要途径中的关键中间体。涉及的主要反应是（1）通过胆甾醇（异戊烷）的3碳延伸形成胆固醇（异辛烷）侧链，（2）氧化序列以转化甾体A的3α-羟基/ B环形成所需的4-en-3-one系统，以及（3）对甾体原子核中C-7和C-12位置的羟基的适当保护策略。1a和1b的绝对结构通过NMR和X射线晶体学确认。从2a和2b分别分11步制备的目标化合物1a和1b，

  DOI：

  10.1016/j.steroids.2013.05.011

文献信息

• [EN] COMPOUNDS USEFUL FOR ALTERING THE LEVELS OF BILE ACIDS FOR THE TREATMENT OF DIABETES AND CARDIOMETABOLIC DISEASE<br/>[FR] COMPOSÉS UTILES POUR MODIFIER LES TAUX D'ACIDES BILIAIRES POUR LE TRAITEMENT DU DIABÈTE ET DE MALADIES CARDIOMÉTABOLIQUES.
  申请人：MERCK SHARP & DOHME

  公开号：WO2018034918A1

  公开（公告）日：2018-02-22

  Described herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula I act as Cyp8b1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for diabetes and cardiovascular disease.

  本文描述了式（I）的化合物或其药用可接受的盐。式（I）的化合物作为Cyp8b1抑制剂，可用于预防、治疗或作为糖尿病和心血管疾病的治疗剂。
• ENZYME COMPOSITIONS, STEROID DERIVATIVES, ENZYME INHIBITORS, AND METHODS OF MAKING SAME FOR PHARMACEUTICAL APPLICATIONS
  申请人：BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US20200172567A1

  公开（公告）日：2020-06-04

  The present disclosure provides for a synthetic strategy to incorporate a C12α-hydroxy group from the methylene (—CH2-) in a steroid backbone, combining synthetic chemistry and enzymology techniques to develop a selective inhibitor for cytochrome P450 8B1, and developing a selective P450 8B1 inhibitor, which can be used as a tool to study P450 8B1 and treat health issues.

  本公开提供一种合成策略，以从类固醇骨架中的亚甲基（—CH2-）中合并C12α-羟基的方式，结合合成化学和酶学技术，开发一种选择性抑制剂，用于细胞色素P450 8B1，并开发一种选择性P450 8B1抑制剂，可用作研究P450 8B1和治疗健康问题的工具。
• The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
  作者：David W. Russell

  DOI：10.1146/annurev.biochem.72.121801.161712

  日期：2003.6

  ▪ Abstract  The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synthesis cause a spectrum of human disease; this ranges from liver failure in early childhood to progressive neuropathy in adults.

  ▪ 摘要：在哺乳动物体内，胆汁酸的合成和排泄构成了胆固醇分解的主要途径。合成提供了一种将既疏水又不溶于水的胆固醇直接转化为水溶性且容易排泄的分子——胆汁酸的直接方法。完成这种转化的生物合成步骤也赋予了胆汁酸的清洁剂特性，这些特性被机体利用来促进从肝脏排泄胆固醇。这种在胆固醇排泄中的作用被胆汁酸溶解膳食胆固醇和必需营养素以及促进它们传递到肝脏的能力所平衡。合成完整的胆汁酸需要17种酶。途径中的选择性酶的表达受到核激素受体和其他转录因子的严格调控，这些因子确保在不断变化的代谢环境中始终有足够的胆汁酸供应。遗传突变会影响胆汁酸的合成，导致一系列人类疾病，从儿童早期的肝衰竭到成年人的渐进性神经病变。
• Structure and Chromosomal Assignment of the Sterol 12α-Hydroxylase Gene (CYP8B1) in Human and Mouse: Eukaryotic Cytochrome P-450 Gene Devoid of Introns
  作者：Mats Gåfvels、Maria Olin、Bhanu P. Chowdhary、Terje Raudsepp、Ulla Andersson、Bengt Persson、Monica Jansson、Ingemar Björkhem、Gösta Eggertsen

  DOI：10.1006/geno.1998.5606

  日期：1999.3

  Sterol 12alpha-hydroxylase (CYP8B1) is a hepatic cytochrome P-450 that controls the ratio of cholic acid over chenodeoxycholic acid in bile and thus controls the solubility of cholesterol. Both the human and the mouse CYP8B1 complementary DNA and gene were cloned and structurally characterized. Surprisingly, the genomic DNA from both species was found to lack introns. The major transcript of the human

  甾醇12α-羟化酶（CYP8B1）是一种肝细胞色素P-450，它控制胆汁中胆酸与鹅去氧胆酸的比例，从而控制胆固醇的溶解度。人和小鼠CYP8B1互补DNA和基因均被克隆并进行结构表征。令人惊讶地，发现两种物种的基因组DNA均缺乏内含子。人基因的主要转录物估计为3950 bp，推定的启动子区域估计至少为1360 bp。发现鼠的结构基因跨越约3kb。通过使用FISH和辐射杂交作图技术，人类CYP8B1基因位于3p21.3-p22染色体，而FISH则将鼠对应物映射至9qF4染色体，该区域与第三条人类染色体同源。染色体作图和Southern印迹的结果表明该基因以单个拷贝存在。小鼠和人CYP8B1基因的转录分别从共有TATA框下游51和35个碱基的位置开始。小鼠和人的启动子区域的21％同源性可能表明转录调控方面存在差异。尽管在小鼠饥饿后观察到强效的CYP8B1 mRNA诱导作用，但通过分析启动子中潜在
• Molecular Cloning and Expression of Rabbit Sterol 12α-Hydroxylase
  作者：Gösta Eggertsen、Maria Olin、Ulla Andersson、Hiroko Ishida、Shunichiro Kubota、Ulf Hellman、Kyu-Ichiro Okuda、Ingemar Björkhem

  DOI：10.1074/jbc.271.50.32269

  日期：1996.12

  enzyme in bile acid biosynthesis, responsible for the balance between formation of cholic acid and chenodeoxycholic acid. The enzyme has been purified to apparent homogeneity from rabbit liver (Ishida, H., Noshiro, M., Okuda, K., and Coon, M. J. (1992) J. Biol. Chem. 267, 21319-21323), and we here describe the cloning and sequencing of a cDNA coding for this enzyme. After tryptic digestion of purified

  甾醇12α-羟化酶是胆汁酸生物合成中的重要酶，负责胆酸和鹅去氧胆酸的形成之间的平衡。该酶已从兔肝中纯化至表观同质性（石田，H。，野代郎，M。，奥田，K。，和库恩，MJ（1992）生物化学杂志，267，21319-21323），我们在这里描述了编码该酶的cDNA的克隆和测序。在聚丙烯酰胺凝胶中胰蛋白酶消化纯化的蛋白质后，分离并测序了八种不同的肽。使用从氨基酸序列推导的寡核苷酸，从兔肝cDNA文库分离克隆。除了几个重叠克隆外，还获得了一个全长克隆，该克隆编码了500个氨基酸的多肽，对应于57 kDa的分子量。所有八个肽和报道的NH 2末端氨基酸序列都与该序列匹配。在整体合成胆汁酸，兔胆固醇7α-羟化酶（CYP7）时，该肽序列与人前列环素合酶（CYP8）有39％的相似性，与限速酶有31％的相似性。与大多数其他固醇细胞色素P-450羟化酶的相似性较低。因此，这种细胞色素P-450物种应属于其自身的