2'-C-甲基5'-胞苷酸 | 386213-38-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 中文名称: 2'-C-甲基5'-胞苷酸
• 英文名称: 2'-C-Methyl 5'-Cytidylic Acid
• 英文别名: [(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methyl dihydrogen phosphate
• CAS: 386213-38-3
• 化学式: C₁₀H₁₆N₃O₈P
• 分子量: 337.226
• InChiKey: ZJFPROVXANKXPJ-VPCXQMTMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  175
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2'-C-甲基胞嘧啶核苷 在 recombinant human deoxycytidine kinase, His-tagged 、 potassium chloride 、 5’-三磷酸腺苷 、 magnesium chloride 、 Cleland's reagent 、 BSA 作用下， 生成 2'-C-甲基5'-胞苷酸
  参考文献：
  名称：

  Evaluation of the role of three candidate human kinases in the conversion of the hepatitis C virus inhibitor 2′-C-methyl-cytidine to its 5′-monophosphate metabolite

  摘要：

  Nucleoside analogs are effective inhibitors of the hepatitis C virus (HCV) in the clinical setting. One such molecule, 2'-C-methyl-cytidine (2'-MeC), entered clinical development as NM283, a valine ester prodrug form of 2'-MeC possessing improved oral bioavailability. To be active against HCV, 2'-MeC must be converted to 2'-MeC triphosphate which inhibits NS5B, the HCV RNA-dependent RNA polymerase. Conversion of 2'-MeC to 2'-MeC monophosphate is the first step in 2'-MeC triphosphate production and is thought to be the rate-limiting step. Here we investigate which of three possible enzymes, deoxycytidine kinase (dCK), uridine-cytidine kinase 1 (UCK1), or uridine-cytidine kinase 2 (UCK2), mediate this first phosphorylation step. Purified recombinant enzymes UCK2 and dCK, but not UCK1, could phosphorylate 2'-MeC in vitro. However, siRNA knockdown experiments in three human cell lines (HeLa, Huh7 and HepG2) defined UCK2 and not dCK as the key kinase for the formation of 2'-MeC monophosphate in cultured human cells. These results underscore the importance of confirming enzymatic kinase data with appropriate cell-based assays. Finally, we present data suggesting that inefficient phosphorylation by UCK2 likely limits the antiviral activity of 2'-MeC against HCV. This paves the way for the use of a nucleotide prodrug approach to overcome this limitation. (C) 2009 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.antiviral.2009.10.020

文献信息

• Metabolically Stable Alkoxyalkyl Esters of Antiviral or Antiproliferative Phosphonates, Nucleoside Phosphonates and Nucleoside Phosphates
  申请人：Hostetler Y. Karl

  公开号：US20080009462A1

  公开（公告）日：2008-01-10

  The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.

  本发明涉及磷酸酯、核苷酸磷酸酯或核苷酸磷酸盐化合物，包含它们的组合物，获得它们的过程以及它们在治疗各种医疗疾病，特别是病毒感染、癌症等方面的用途。
• Cyclic phosphoramidates as prodrugs of 2′-C-methylcytidine
  作者：Malte Meppen、Barbara Pacini、Renzo Bazzo、Uwe Koch、Joseph F. Leone、Kenneth A. Koeplinger、Michael Rowley、Sergio Altamura、Annalise Di Marco、Fabrizio Fiore、Claudio Giuliano、Odalys Gonzalez-Paz、Ralph Laufer、Vincenzo Pucci、Frank Narjes、Cristina Gardelli

  DOI：10.1016/j.ejmech.2009.04.043

  日期：2009.9

  The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2'-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes. (C) 2009 Elsevier Masson SAS. All rights reserved.
• METABOLICALLY STABLE ALKOXYALKYL ESTERS OF ANTIVIRAL OR ANTIPROLIFERATIVE PHOSPHONATES, NUCLEOSIDE PHOSPHONATES AND NUCLEOSIDE PHOSPHATES
  申请人：Chimerix, Inc.

  公开号：EP2012799A2

  公开（公告）日：2009-01-14
• US7749983B2
  申请人：——

  公开号：US7749983B2

  公开（公告）日：2010-07-06
• US7994143B2
  申请人：——

  公开号：US7994143B2

  公开（公告）日：2011-08-09