[(2R,3R,4R,5R,6R)-5-acetamido-6-[5-[3-[3-[3-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]-2-[[12-[(2S,4R)-2-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxypyrrolidin-1-yl]-12-oxododecanoyl]amino]propoxy]propanoylamino]propylamino]-5-oxopentoxy]-3,4-diacetyloxyoxan-2-yl]methyl acetate | 1159408-72-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: [(2R,3R,4R,5R,6R)-5-acetamido-6-[5-[3-[3-[3-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]-2-[[12-[(2S,4R)-2-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxypyrrolidin-1-yl]-12-oxododecanoyl]amino]propoxy]propanoylamino]propylamino]-5-oxopentoxy]-3,4-diacetyloxyoxan-2-yl]methyl acetate
• CAS: 1159408-72-6
• 化学式: C₁₁₇H₁₇₅N₁₁O₄₂
• 分子量: 2407.72
• InChiKey: GGDUVQWHSIEKKC-LJNDWZPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.35
• 重原子数：
  170.0
• 可旋转键数：
  80.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  679.0
• 氢给体数：
  11.0
• 氢受体数：
  42.0

反应信息

• 作为反应物：
  描述：

  丁二酸酐 、 [(2R,3R,4R,5R,6R)-5-acetamido-6-[5-[3-[3-[3-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]-2-[[12-[(2S,4R)-2-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxypyrrolidin-1-yl]-12-oxododecanoyl]amino]propoxy]propanoylamino]propylamino]-5-oxopentoxy]-3,4-diacetyloxyoxan-2-yl]methyl acetate 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 GalNAc-L96 free base
  参考文献：
  名称：

  [EN] CONJUGATES AND PREPARATION AND USE THEREOF
  [FR] CONJUGUÉS ET PRÉPARATION ET UTILISATION ASSOCIÉES

  摘要：

  揭示了一种用于与活性剂形成共轭物的化合物，例如具有由公式（321）表示的结构的寡核苷酸，并且相应的共轭物。该共轭物可以特异性地靶向肝细胞，因此有效地解决了与体内寡核苷酸药物传递相关的问题，并且在保持传递的寡核苷酸高稳定性的同时具有低毒性和出色的传递效率。

  公开号：

  WO2019128611A1
• 作为产物：
  描述：

  Tri-GalNAc(OAc)3 TFA 、 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以88%的产率得到[(2R,3R,4R,5R,6R)-5-acetamido-6-[5-[3-[3-[3-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]-2-[[12-[(2S,4R)-2-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxypyrrolidin-1-yl]-12-oxododecanoyl]amino]propoxy]propanoylamino]propylamino]-5-oxopentoxy]-3,4-diacetyloxyoxan-2-yl]methyl acetate
  参考文献：
  名称：

  CARBOHYDRATE CONJUGATES AS DELIVERY AGENTS FOR OLIGONUCLEOTIDES

  摘要：

  本发明提供了包含至少一个式(I)的亚单位的iRNA试剂： 其中： A和B分别独立于每次出现O、N(RN)或S； X和Y分别独立于每次出现H、OH、一个羟基保护基团、一个磷酸基团、一个磷酸二酯基团、一个活化磷酸基团、一个活化亚磷酸基团、一个磷酰胺基团、一个固相支持、-P(Z')(Z″)O-核苷、-P(Z')(Z″)O-寡核苷酸、一个脂质、一个PEG、一个类固醇、一个亲脂物质、一个聚合物、-P(Z')(Z″)O-连接子-OP(Z′″)(Z″″)O-寡核苷酸、一个核苷酸、一个寡核苷酸、-P(Z')(Z″)-式(I)、-P(Z')(Z″)-或-连接子-R； R是LG、-连接子-LG，或具有下面所示结构： LG独立于每次出现的是一种碳水化合物，例如，单糖、双糖、三糖、四糖、寡糖、多糖； RN独立于每次出现的是H、甲基、乙基、丙基、异丙基、丁基或苄基； Z'、Z″、Z′″和Z″″分别独立于每次出现的是O或S。

  公开号：

  US20160051691A1

文献信息

• NUCLEIC ACID, COMPOSITION AND CONJUGATE CONTAINING NUCLEIC ACID, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：SUZHOU RIBO LIFE SCIENCE CO., LTD.

  公开号：US20220062427A1

  公开（公告）日：2022-03-03

  Provided are an siRNA for inhibiting the expression of the apolipoprotein C3 gene, and a pharmaceutical composition and a conjugate containing the siRNA. Each nucleotide in the siRNA is, respectively and independently, a modified or unmodified nucleotide; the siRNA contains a sense strand and an anti-sense strand; the sense strand includes nucleotide sequence I; nucleotide sequence I has the same length as the nucleotide sequence as shown in SEQ ID NO: 1, and not more than three nucleotides are different; the anti-sense strand contains nucleotide sequence II; and nucleotide sequence II has the same length as the nucleotide sequence as shown in SEQ ID NO: 2, and not more than three nucleotides are different. The siRNA provided by the present disclosure and the pharmaceutical composition and the conjugate thereof can effectively treat and/or prevent dyslipidemia.

  提供了一种siRNA，用于抑制载脂蛋白C3基因的表达，以及含有siRNA的药物组合物和共轭物。siRNA中的每个核苷酸分别且独立地是修饰或未修饰的核苷酸；siRNA包含一个正义链和一个反义链；正义链包括核苷酸序列I；核苷酸序列I与SEQ ID NO: 1所示的核苷酸序列长度相同，且不超过三个核苷酸不同；反义链包含核苷酸序列II；核苷酸序列II与SEQ ID NO: 2所示的核苷酸序列长度相同，且不超过三个核苷酸不同。本公开提供的siRNA及其药物组合物和共轭物可以有效治疗和/或预防血脂异常。
• Multivalent <i>N</i>-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing
  作者：Jayaprakash K. Nair、Jennifer L. S. Willoughby、Amy Chan、Klaus Charisse、Md. Rowshon Alam、Qianfan Wang、Menno Hoekstra、Pachamuthu Kandasamy、Alexander V. Kel’in、Stuart Milstein、Nate Taneja、Jonathan O’Shea、Sarfraz Shaikh、Ligang Zhang、Ronald J. van der Sluis、Michael E. Jung、Akin Akinc、Renta Hutabarat、Satya Kuchimanchi、Kevin Fitzgerald、Tracy Zimmermann、Theo J. C. van Berkel、Martin A. Maier、Kallanthottathil G. Rajeev、Muthiah Manoharan

  DOI：10.1021/ja505986a

  日期：2014.12.10

  Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.