乙炔基胞苷 | 180300-43-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: 乙炔基胞苷
• 中文别名: 乙炔基
• 英文名称: 3'-ethynylcytidine
• 英文别名: ECyd；1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine；1-[3-C-ethynyl-β-D-ribo-pentofuranosyl]cytosine；1-(3-C-ethynyl-β-D-ribopentofuranosyl)cytosine；1-(3-C-ethynyl-β-D-ribofuranosyl)cytosine；3'-C-ethynylcytidine；4-amino-1-[(2R,3R,4S,5R)-4-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
• CAS: 180300-43-0
• 化学式: C₁₁H₁₃N₃O₅
• 分子量: 267.241
• InChiKey: JFIWEPHGRUDAJN-DYUFWOLASA-N

物化性质

• 熔点：
  233-235 °C
• 沸点：
  536.4±60.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:127.5(最大浓度 mg/mL);477.1(最大浓度 mM)DMF:5.0(最大浓度 mg/mL);18.71(最大浓度 mM)PBS (pH 7.2) ):10.0(最大浓度 mg/mL);37.42(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.7
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  129
• 氢给体数：
  4
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃

制备方法与用途

生物活性

Ethynylcytidine (ECyD) 是一种核苷类似物，有效抑制 RNA 合成（RNA synthesis），能抑制 RNA 聚合酶 I、II 和 III。在多种癌症模型中，Ethynylcytidine 均表现出强大的抗肿瘤活性。

靶点

• Nucleoside antimetabolite

体外研究

在五种人类肿瘤细胞系中的 Ethynylcytidine 的半抑制浓度 (IC₅₀) 在不同暴露时间（4 小时、24 小时和 72 小时）下分别为：0.114 至 1.032 微摩尔、0.015 至 0.067 微摩尔以及 0.008 至 0.058 微摩尔。这些结果表明，随着暴露时间的延长，Ethynylcytidine 的细胞毒性作用会增强。24 小时和 72 小时暴露时间下的 IC₅₀ 值差异不大，在所有五种人类肿瘤中，其在 24 小时暴露时表现出充分的细胞毒性。即使在 4 小时暴露时间内，Ethynylcytidine 在四种人类肿瘤中的 IC₅₀ 值也处于亚微摩尔浓度，并且显示出明显的细胞毒性。

体内研究

在 OCUM-2MD3 和 LX-1 的异种移植模型中，最低毒剂量 Ethynylcytidine (TAS-106) 在所有三种给药方案下均观察到肿瘤缩小。特别是在每周一次、每次 6 毫克/千克的给药方式下，对 LX-1 肿瘤表现出强烈的抗肿瘤效果，抑制率（IR）达到约 98%。而在每三或五天一次的给药计划中，Ethynylcytidine 的抗肿瘤作用仍然显著，抑制率为约 85%，但每周一次的给药方式则效果较弱，抑制率低于 60%。

反应信息

• 作为反应物：
  描述：

  乙炔基胞苷 在 还原型辅酶II(NADPH)四钠盐 4-二甲氨基吡啶 、 高氯酸 、 rat liver S-9 、 硫酸 、 potassium chloride 、 sodium methylate 、 三乙胺 、 三氟乙酸 、 magnesium chloride 作用下， 以 甲醇 、 水 、 丙酮 、 甲苯 、 乙腈 为溶剂， 反应 14.17h， 生成 1-[3-C-ethynyl-2,3-O-(3-aminobenzylidene)-β-D-ribo-pentofuranosyl]cytosine
  参考文献：
  名称：

  Synthesis of the cyclic and acyclic acetal derivatives of 1-(3-C-Ethynyl-β-d-ribo-pentofuranosyl)cytosine, a potent antitumor nucleoside. Design of prodrugs to be selectively activated in tumor tissues via the bio-Reduction–Hydrolysis mechanism☆

  摘要：

  We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2',3'-O-nitrobenzylidene derivatives 2 and 3 and the 5'-O-(alkoxy)(nitrophenyl)methyl derivatives 6-10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2',3'-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5'-O-(alkoxy)(4-nitropheny)methyl derivatives 6-8 were also reduced by rat S-9 mix to the corresponding amino congeners 11-13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6-8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00104-4
• 作为产物：
  描述：

  1-{5-O-(4-chlorobenzoyl)-2,3-di-O-isobutyryl-3-C-[2-(trimethylsilyl)ethynyl]-β-D-ribopentofuranosyl}cytosine 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以68%的产率得到乙炔基胞苷
  参考文献：
  名称：

  Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction

  摘要：

  A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-beta-C-ethynyl glycosyl donors in the key Vorbruggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(01)01249-2

文献信息

• [EN] COMPOSITIONS AND METHODS FOR SYNTHESIS OF PHOSPHORYLATED MOLECULES<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE SYNTHÈSE DE MOLÉCULES PHOSPHORYLÉES
  申请人：UNIV CALIFORNIA

  公开号：WO2019195494A1

  公开（公告）日：2019-10-10

  The invention provides compositions and methods for synthesis of phosphorylated organic compounds, including nucleoside triphosphates.

  这项发明提供了合成磷酸化有机化合物的组合物和方法，包括核苷三磷酸。
• Nucleotide mimics and their prodrugs
  申请人：——

  公开号：US20040059104A1

  公开（公告）日：2004-03-25

  The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

  本发明涉及核苷二磷酸模拟物和核苷三磷酸模拟物，其中包含二磷酸或三磷酸基团模拟物，以及可选的糖修饰和/或碱基修饰。本发明的核苷酸模拟物，以药学上可接受的盐、药学上可接受的前药或药物配方的形式，可用作抗病毒、抗微生物和抗癌剂。本发明提供了一种治疗病毒感染、微生物感染和增生性疾病的方法。本发明还涉及包含本发明化合物的药物组合物，可选地与其他药理活性剂结合。
• AGENT FOR PREVENTING OR TREATING PANCREAS CANCER, OVARY CANCER OR LIVER CANCER CONTAINING NOVEL WATER-SOLUBLE PRODRUG
  申请人：CHUGAI SEIYAKU KABUSHIKI KAISHA

  公开号：EP1938823A1

  公开（公告）日：2008-07-02

  Preventive or therapeutic agents for pancreatic cancer, ovarian cancer, or liver cancer of the present invention comprise a water-soluble prodrug represented by formula 1 described below, or a pharmaceutically acceptable salt, or a hydrate or solvate of the prodrug or pharmaceutically acceptable salt, (wherein, R1 represents a hydrogen atom, or a C1-C6 alkyl group; W represents a divalent group comprising a tertiary amino group or a divalent group comprising a sulfonyl group, and Y represents a residue of a compound represented by Y-OH comprising an alcoholic hydroxyl group, wherein said Y-OH is a camptothecin, a taxane, or an anticancer nucleotide).

  预防或治疗胰腺癌、卵巢癌或肝癌的本发明药剂包括下述式子所代表的水溶性前药，或者前药的药用可接受盐，或者前药或药用可接受盐的水合物或溶剂化合物， （其中， R1代表氢原子，或者C1-C6烷基； W代表包含三级胺基团或含磺酰基团的二价基团，以及 Y代表由Y-OH所代表的化合物残基，包括含有醇羟基的醇羟基化合物残基，其中所述的Y-OH是一种喜树碱、紫杉醇或抗癌核苷酸）。
• [EN] COMPOSITIONS AND METHODS FOR DELIVERY OF THERAPEUTIC AGENTS<br/>[FR] COMPOSITIONS ET PROCÉDÉS PERMETTANT D'ADMINISTRER DES AGENTS THÉRAPEUTIQUES
  申请人：MODERNATX INC

  公开号：WO2017099823A1

  公开（公告）日：2017-06-15

  This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering agents in vivo including nucleic acids and proteins. These compositions are not subject to accelerated blood clearance and they have an improved toxicity profile in vivo.

  这项披露提供了改进的基于脂质的组合物，包括脂质纳米粒子组合物，以及它们用于体内传递药剂的方法，包括核酸和蛋白质。这些组合物不受加速血清清除的影响，并且它们在体内具有改进的毒性特性。
• A New Laboratory Scale Synthesis for the Anticancer Drug 3′<i>-C-</i>Ethynylcytidine­
  作者：Peter S. Ludwig、Reto A. Schwendener、Herbert Schott

  DOI：10.1055/s-2002-35221

  日期：——

  A new synthetic route for the preparation of larger quan- tities of the anticancer nucleoside analogue 3 -C-ethynylcytidine is described. Starting from cytidine which was orthogonally protected in three steps, the ketonucleoside analogue as the key intermediate was obtained through oxidation of the unprotected 3 -hydroxy group. Stereoselective addition of the trimethylsilyl-protected acetylide residue

  描述了制备大量抗癌核苷类似物 3-C-乙炔基胞苷的新合成路线。以三步正交保护的胞苷为原料，通过氧化未保护的3-羟基得到酮核苷类似物作为关键中间体。在 3-羰基上立体选择性加成三甲基甲硅烷基保护的乙炔残基，然后完全脱保护，在 7 个步骤中以 24% 的总产率得到 3-C-乙炔基胞苷。乙炔化核糖核苷类似物已显示出它们在体外和体内对多种不同细胞系以及肿瘤模型的抗肿瘤潜力。1 这些测试结果表明 1-(3-C-ethynyl--D-ribopentafuranosyl) 胞嘧啶 (3-C-ethynylcytidine, ECyd）作为这一新药物类别中最有希望的代表，已进入实体瘤患者的 I 2 期临床试验。由于其抗肿瘤潜力 1 和独特的作用机制 3,4，我们认为 ECyd 可能是新开发的抗癌药物的新关键结构，具有通过衍生这种母体核苷类似物获得的优化抗肿瘤潜力。这激发了对以制备量和高产率制备ECyd的