3α,7β-diformyloxy-5β-cholan-24-oic acid | 6159-50-8

• 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
• 英文名称: 3α,7β-diformyloxy-5β-cholan-24-oic acid
• 英文别名: Ursodesoxycholic Acid Diformate；(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-diformyloxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• CAS: 6159-50-8
• 化学式: C₂₆H₄₀O₆
• 分子量: 448.6
• InChiKey: LMKQATDCJXKIJD-LBSADWJPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3α,7β-diformyloxy-5β-cholan-24-oic acid 在 三氟乙酸 、 三氟乙酸酐 、 potassium hydroxide 、 sodium nitrite 作用下， 以 甲醇 、 水 为溶剂， 反应 57.0h， 生成 24-去甲熊脱氧胆酸
  参考文献：
  名称：

  Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)

  摘要：

  Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3 alpha,7 beta-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of proglucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.

  DOI：

  10.1021/jm500889f
• 作为产物：
  描述：

  3Α-羟基-7-氧代-5Β-胆烷酸 在 盐酸 、 溶剂黄146 、 铂 作用下， 生成 3α,7β-diformyloxy-5β-cholan-24-oic acid
  参考文献：
  名称：

  Miyazi, Hoppe-Seyler's Zeitschrift fur Physiologische Chemie, 1937, vol. 250, p. 31

  摘要：

  DOI：

文献信息

• Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to <i>Clostridium difficile</i> Spore Germination
  作者：Kristen L. Stoltz、Raymond Erickson、Christopher Staley、Alexa R. Weingarden、Erin Romens、Clifford J. Steer、Alexander Khoruts、Michael J. Sadowsky、Peter I. Dosa

  DOI：10.1021/acs.jmedchem.7b00295

  日期：2017.4.27

  bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were

  基于标准抗生素的难治性梭状芽孢杆菌感染的治疗策略会破坏原生菌群，并且通常无法根除细菌孢子，这是导致感染复发的两个关键因素。作为控制艰难梭菌的替代方法感染后，已制备了一系列抑制牛磺胆酸盐诱导的孢子萌发的胆汁酸衍生物。这些类似物已使用光密度和相差显微镜分析法在高毒性NAP1菌株中进行了评估。在两种测定中，C24的杂环取代均具有良好的耐受性，几种含四唑的衍生物是高效抑制剂，在10–25μM时可完全抑制孢子萌发。为了限制肠道吸收，制备了旨在避免主动和被动转运途径的C7硫酸盐类似物。发现这些衍生物之一化合物21b是强效梭状芽胞杆菌的有效抑制剂。 Caco-2肠上皮吸收模型中的孢子萌发和渗透性差，表明它很可能受到肠道限制。
• The preparation of bile acid amides and oxazolines, II, the synthesis of the amides and oxazolines of ursodeoxycholic acid, deoxycholic acid, hyodeoxycholic acid and cholic acid
  作者：Bertram I. Cohen、Patricia S. May、Charles K. McSherry、Erwin H. Mosbach

  DOI：10.1016/0039-128x(82)90011-3

  日期：1982.12

  Bile acid amides and oxazolines were synthesized by a sequence of steps involving the reaction of the free bile acid with formic acid to yield the formyloxy derivative, preparation of the formyloxy acid chloride, condensation of the acid chloride with 2-amino-2-methyl-1-propanol to give the amide and, finally, cyclization of the amide with thionyl chloride to give the oxazoline. The oxazolines were

  胆汁酰胺和恶唑啉是通过一系列步骤合成的，这些步骤包括游离胆汁酸与甲酸反应生成甲酰氧基衍生物，制备甲酰氧基酰氯，酰氯与2-氨基-2-甲基-氯的缩合。 1-丙醇得到酰胺，最后用亚硫酰氯将酰胺环化得到恶唑啉。通过物理常数，薄层色谱和气液色谱法对恶唑啉进行表征，并通过元素分析和气液色谱-质谱法对其进行鉴定。一些胆汁酸恶唑啉衍生物可在体外改变细菌7-脱羟基酶的活性，并在纯培养物中抑制某些厌氧菌的生长。
• 24-nor-5β-chol-22-enes derived from the major bile acids by oxidative decarboxylation
  作者：Gerald L. Carlson、Don T.E. Belobaba、Alan F. Hofmann、Yuri Wedmid

  DOI：10.1016/s0039-128x(77)80024-x

  日期：1977.12

  The preparation of 24-nor-5beta-chol-22-enes from formyloxy-5beta-cholanic acids by oxidative decarboxylation with lead tetraacetate is described. NMR data is presented with other physical constants for the norcholenes derived from cholic, chenodeoxycholic, ursodeoxycholic, hyodeoxycholic, and deoxycholic acids. The facile synthesis of these norcholenes demonstrates the applicability of the formyloxy

  描述了通过用四乙酸铅氧化脱羧从甲酰氧基-5β-胆酸制备24-nor-5β-chol-22-烯。NMR数据与衍生自胆酸，鹅去氧胆酸，熊去氧胆酸，猪去氧胆酸和脱氧胆酸的降冰片烯的其他物理常数一起显示。这些降冰片烯的简便合成证明了甲酰氧基保护基在胆汁酸系列中对氧化脱羧的适用性。
• Synthesis, characterization and biological activity of hydroxyl-bisphosphonic analogs of bile acids
  作者：Olga Bortolini、Giancarlo Fantin、Marco Fogagnolo、Stefano Rossetti、Loredana Maiuolo、Gemma Di Pompo、Sofia Avnet、Donatella Granchi

  DOI：10.1016/j.ejmech.2012.03.020

  日期：2012.6

  enhanced by the presence of bile acid substituents in the bisphosphonate framework, with no toxic effects. A straightforward synthesis of bile acid-containing hydroxy-bisphosphonates and a full characterization of these pharmaceutically important molecules, including an evaluation of affinity and the mechanism of binding to hydroxyapatite, is presented. The biological activity of bile acid-containing bisphosphonate

  现在，双膦酸盐（BPs）是用于与骨吸收增加有关的疾病（例如骨质疏松症和肿瘤性骨病）的最广泛使用的药物。BP的一个显着缺点是口服吸收差，双膦酸盐骨架中胆汁酸取代基的存在会增强它们的口服吸收，而没有毒性作用。提出了含胆汁酸的羟基双膦酸酯的直接合成方法和这些药学上重要分子的完整表征，包括亲和力评估和与羟基磷灰石的结合机理。使用中性红测定法在L929细胞系和破骨细胞的原代培养物中测定了含胆汁酸的双膦酸盐的生物活性。发现新化合物的生物活性优于已确定活性的双膦酸酯。
• Quantitative Relationship between Bile Acid Structure and Biliary Lipid Secretion in Rats
  作者：A. Roda、B. Grigolo、E. Roda、P. Simoni、R. Pellicciari、B. Natalini、A. Fini、A. M. Morselli Labate

  DOI：10.1002/jps.2600770710

  日期：1988.7

  series of unconjugated and taurine conjugated bile acids (BAs) differing in water solubility (SWo), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 mumol/min/kg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids secretions, and bile flow. The BAs studied differ in the number

  将一系列示踪剂剂量为6 mumol / min的静脉输注一系列水溶性（SWo），临界胶束浓度（CMC）和亲水性（K'）不同的非共轭和牛磺酸共轭胆汁酸（BAs） / kg在1小时内。收集胆汁3小时，以评估BA结构对胆固醇，磷脂分泌和胆汁流动的作用。研究的BA的数量（2-3），位置（-3，-6，-7，-12）和羟基的方向（alpha / beta）不同；通过缩短（C-23，nor-BA）和延长（C-25，homo-BA）修饰侧链结构，同时保持相同的核羟基结构（3 alpha 7 beta）。以“示踪剂”剂量，当以非结合形式和牛磺酸结合形式同时给药时，所有C-24天然BAs都可以在胆汁中有效地回收。在“高剂量”下，所有牛磺酸缀合的BA均能在胆汁中有效回收（80-100％）。但是，在未结合的BA之间观察到了可变的回收率：三羟基BA被有效回收（85-100％），而二羟基BA仅被部分回收（25-40％）。侧链修饰的BA