异胆酸甲酯-d7 | 5405-42-5

• 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: 异胆酸甲酯-d7
• 英文名称: methyl 3β-hydroxy-5β-cholan-24-oate
• 英文别名: methyl iso-lithocholate；3beta-Hydroxy-5beta-cholan-24-oic acid Methyl ester；methyl (4R)-4-[(3S,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate
• CAS: 5405-42-5
• 化学式: C₂₅H₄₂O₃
• 分子量: 390.607
• InChiKey: YXZVCZUDUJEPPK-ARCWCCGYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  异胆酸甲酯-d7 在 吡啶 、 1,3-丙二硫醇 、 sodium azide 、 三乙胺 作用下， 以 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.0h， 生成 3β-aminolithocholic acid methyl ester
  参考文献：
  名称：

  Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asialoglycoprotein Receptor

  摘要：

  A novel glycolipid has been prepared that contains a cluster glycoside with an unusually high affinity for the asialoglycoprotein receptor (ASGPr) and a bile acid moiety that mediates stable incorporation into lipidic particles. The glycolipid spontaneously associated with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) within human and murine plasma, and loading of lipoproteins with this glycolipid resulted in an efficient dose-dependent recognition and uptake of LDL and HDL by the liver (and not by spleen) upon intravenous injection into wild-type mice. Preinjection with asialoorosomucoid largely inhibited the uptake, establishing that both HDL and LDL were selectively recognized and processed by the ASGPr on liver parenchymal cells. Finally, repeated intravenous administration of the glycolipid to hyperlipidemic LDL receptor-deficient mice evoked an efficient and persistent cholesterol-lowering effect. These results indicate that the glycolipid may be a promising alternative for the treatment of hyperlipidemic patients who do not respond sufficiently to current cholesterol-lowering therapies.

  DOI：

  10.1021/jm049481d
• 作为产物：
  描述：

  methyl 3β-formyloxy-5β-cholan-24-oate 在 sodium methylate 作用下， 以 甲醇 为溶剂， 以98%的产率得到异胆酸甲酯-d7
  参考文献：
  名称：

  类固醇环肽，腔体的合成和形状

  摘要：

  从石胆酸和（S）-苯丙氨酸合成了环-[3α-（苯丙氨酰氨基）-5β-胆酸盐] 2 2。该合成需要三个转化：i）3α-羟基向3α-氨基的立体选择性转化；ii）制备线性甾体肽；iii）环二聚。NMR测量和MM3计算支持亲脂性空腔为2的构象。

  DOI：

  10.1016/s0040-4039(00)75839-4

文献信息

• [EN] NMDAR INHIBITING AGENTS AND GABAAR POTENTIATING AGENTS AND USES THEREOF<br/>[FR] AGENTS INHIBITEURS DE NMDAR ET AGENTS DE POTENTIALISATION GABAAR ET LEURS UTILISATIONS
  申请人：COVEY DOUGLAS

  公开号：WO2021080880A1

  公开（公告）日：2021-04-29

  N-methyl-d-aspartate receptors (NMDAR) and/or potentiating y-aminobutyric acid receptors (GABAAR) agents and uses thereof are described. Uses of these agents include methods of treating or preventing various psychiatric diseases, disorders, or conditions and methods of treating or preventing alcohol use disorder in a subject in need thereof.

  描述了N-甲基-d-天冬氨酸受体（NMDAR）和/或增强γ-氨基丁酸受体（GABAAR）药物及其用途。这些药物的用途包括治疗或预防各种精神疾病、障碍或病况的方法，以及治疗或预防需要的受试者中的酒精使用障碍的方法。
• Anchoring Cationic Amphiphiles for Nucleotide Delivery Significance of DNA Release from Cationic Liposomes for Transfection
  作者：Naohide Hirashima、Kazuhiro Minatani、Yoshifumi Hattori、Tomohiko Ohwada、Mamoru Nakanishi

  DOI：10.1248/bpb.30.1117

  日期：——

  We have designed and synthesized lithocholic acid-based cationic amphiphile molecules as components of cationic liposomes for gene transfection (lipofection). To study the relationship between the molecular structures of those amphiphilic molecules, particularly the extended hydrophobic appendant (anchor) at the 3-hydroxyl group, and transfection efficiency, we synthesized several lithocholic and isolithocholic acid derivatives, and examined their transfection efficiency. We also compared the physico-chemical properties of cationic liposomes prepared from these derivatives. We found that isolithocholic acid derivatives exhibit higher transfection efficiency than the corresponding lithocholic acid derivatives. This result indicates that the orientation and extension of hydrophobic regions influence the gene transfection process. Isolithocholic acid derivatives showed a high ability to encapsulate DNA in a compact liposome–DNA complex and to protect it from enzymatic degradation. Isolithocholic acid derivatives also facilitated the release of DNA from the liposome–DNA complex, which is a crucial step for DNA entry into the nucleus. Our results show that the transfection efficiency is directly influenced by the ability of the liposome complex to release DNA, rather than by the DNA-encapsulating ability. Molecular modeling revealed that isolithocholic acid derivatives take relatively extended conformations, while the lithocholic acid derivatives take folded structures. Thus, the efficiency of release of DNA from cationic liposomes in the cytoplasm, which contributes to high transfection efficiency, appears to be dependent upon the molecular shape of the cationic amphiphiles.

  我们设计并合成了以石胆酸为基础的阳离子两性分子，作为阳离子脂质体中基因转染（脂质转染）的组成部分。为了研究这些两性分子分子结构之间的关系，尤其是3-羟基基团处的延伸疏水附加物（锚）与转染效率之间的关系，我们合成了几种石胆酸和异石胆酸的衍生物，并检查了它们的转染效率。我们还比较了由这些衍生物制备的阳离子脂质体的物理化学性质。我们发现，异石胆酸衍生物的转染效率高于相应的石胆酸衍生物。这一结果表明，疏水区域的朝向和延伸影响了基因转染过程。异石胆酸衍生物展现出高能力在紧凑的脂质体–DNA复合物中包裹DNA，并保护其免受酶的降解。异石胆酸衍生物还促进了DNA从脂质体–DNA复合物的释放，这对于DNA进入细胞核是一个关键步骤。我们的结果表明，转染效率直接受脂质体复合物释放DNA能力的影响，而不是DNA包裹能力的影响。分子建模显示，异石胆酸衍生物呈现出相对延伸的构象，而石胆酸衍生物则呈现折叠的结构。因此，高转染效率所需的DNA从细胞质中阳离子脂质体释放的效率似乎依赖于阳离子两性分子的分子形状。
• Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators
  作者：Zhao Dang、Kathy Jung、Keduo Qian、Kuo-Hsiung Lee、Li Huang、Chin-Ho Chen

  DOI：10.1021/ml3001962

  日期：2012.11.8

  derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC50 of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an α to β orientation transformed the activator

  由于蛋白酶体活性降低，异常蛋白质聚集体的积累，例如淀粉样蛋白 β 肽 (Aβ)，可能会导致阿尔茨海默病的神经变性。在这项研究中，发现石胆酸衍生物3α- O-庚二酰-石胆酸甲酯 ( 2 ) 及其等排异构体 ( 6 ) 分别以7.8 和 4.3 μM的 EC 50激活蛋白酶体的糜蛋白酶样活性. 在更换C24甲基酯2与甲酰胺导致完全没有蛋白酶体激活活性。将 C3 取代基从 α 到 β 方向差向异构化将激活剂转化为蛋白酶体抑制剂。与细胞蛋白酶体激活剂 PA28 不同，被2激活的蛋白酶体不受 Aβ 抑制。此外，2有效地拮抗 Aβ 对蛋白酶体的抑制作用。总之，化合物2代表了一类新的小分子，不仅可以激活蛋白酶体，还可以拮抗Aβ对蛋白酶体的抑制作用。
• Optimization of EphA2 antagonists based on a lithocholic acid core led to the identification of UniPR505, a new 3α-carbamoyloxy derivative with antiangiogenetic properties
  作者：Matteo Incerti、Simonetta Russo、Miriam Corrado、Carmine Giorgio、Vigilio Ballabeni、Paola Chiodelli、Marco Rusnati、Laura Scalvini、Donatella Callegari、Riccardo Castelli、Federica Vacondio、Francesca Ferlenghi、Massimiliano Tognolini、Alessio Lodola

  DOI：10.1016/j.ejmech.2020.112083

  日期：2020.3

  The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5β-cholan-24-oic acids and 5β-cholan-24-oyl l-β-homotryptophan conjugates, with the aim to

  EphA2受体已在动物模型中被验证为根据血管生成和血管生成模拟物治疗肿瘤的新靶标。在当前的工作中，我们扩展了我们对EphA2受体的两个相关类别拮抗剂的结构-活性关系（SAR）数据的现有知识，即5β-cholan-24-oicacid和5β-cholan-24-oyll-β -纯色氨酸缀合物，旨在开发能够有效防止血管形成的新型抗血管生成化合物。作为我们探索的结果，我们确定了UniPR505 N- [3α-（乙基氨基甲酰基）氧基-5β-cholan-24-oyl]-β-homo-tryptophan（化合物14）是EphA2受体的亚微摩尔拮抗剂。能够在绒膜尿囊膜（CAM）分析中阻断EphA2磷酸化并抑制新血管形成。
• The application of dimethyldioxirane for the selective oxidation of polyfunctional steroids
  作者：Tomoaki Sasaki、Ryusei Nakamori、Takeru Yamaguchi、Yuka Kasuga、Takashi Iida、Toshio Nambara

  DOI：10.1016/s0009-3084(00)00209-7

  日期：2001.2

  Oxidation and epoxidation reactions of a series of structurally different steroids related to methyl 5 beta-cholanoates having hydroxyl groups and/or double bonds by treatment with dimethyldioxirane (DMDO) are described. Steroidal alcohols, olefines, and unsaturated alcohols and conjugated enones with DMDO were transformed into ketones, epoxides, and epoxy-ketones, respectively, in good isolated yields

  描述了通过用二甲基二环氧乙烷（DMDO）处理，与具有羟基和/或双键的5β-胆酸甲酯相关的一系列结构不同的类固醇的氧化和环氧化反应。甾烷醇，烯烃和不饱和醇以及具有DMDO的共轭烯酮分别以良好的分离收率转化为酮，环氧化物和环氧酮。还讨论了DMDO反应的区域选择性和立体选择性与有机过酸，叔丁基氢过氧化物和碱性过氧化氢所观察到的不同。