2,6-Dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbaldehyde O-methyl-oxime

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2,6-Dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbaldehyde O-methyl-oxime
• 英文别名: (E)-Uracil-6-carbaldehyde O-methyl oxime (19)；6-[(E)-methoxyiminomethyl]-1H-pyrimidine-2,4-dione
• 化学式: C₆H₇N₃O₃
• 分子量: 169.14
• InChiKey: HKQWXQNDDZCHHF-XVNBXDOJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  79.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  尿嘧啶-6-甲醛单水合物 、 甲氧基胺盐酸盐 在 sodium acetate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 以62%的产率得到2,6-Dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbaldehyde O-methyl-oxime
  参考文献：
  名称：

  Uracil-Directed Ligand Tethering:  An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development

  摘要：

  Uracil DNA glycosylase (UNG) is an important DNA repair enzyme that recognizes and excises uracil bases in DNA using an extrahelical recognition mechanism. It is emerging as a desirable target for small-molecule inhibitors given its key role in a wide range of biological processes including the generation of antibody diversity, DNA replication in a number of viruses, and the formation of DNA strand breaks during anticancer drug therapy. To accelerate the discovery of inhibitors of UNG we have developed a uracil-directed ligand tethering strategy. In this efficient approach, a uracil aldehyde ligand is tethered via alkyloxyamine linker chemistry to a diverse array of aldehyde binding elements. Thus, the mechanism of extrahelical recognition of the uracil ligand is exploited to target the UNG active site, and alkyloxyamine linker tethering is used to randomly explore peripheral binding pockets. Since no compound purification is required, this approach rapidly identified the first small-molecule inhibitors of human UNG with micromolar to submicromolar binding affinities. In a surprising result, these uracil-based ligands are found not only to bind to the active site but also to bind to a second uncompetitive site. The weaker uncompetitive site suggests the existence of a transient binding site for uracil during the multistep extrahelical recognition mechanism. This very general inhibitor design strategy can be easily adapted to target other enzymes that recognize nucleobases, including other DNA repair enzymes that recognize other types of extrahelical DNA bases.

  DOI：

  10.1021/ja055846n

文献信息

• WO2006/135763
  申请人：——

  公开号：——

  公开（公告）日：——
• Uracil-Directed Ligand Tethering:  An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development
  作者：Yu Lin Jiang、Daniel J. Krosky、Lauren Seiple、James T. Stivers

  DOI：10.1021/ja055846n

  日期：2005.12.1

  Uracil DNA glycosylase (UNG) is an important DNA repair enzyme that recognizes and excises uracil bases in DNA using an extrahelical recognition mechanism. It is emerging as a desirable target for small-molecule inhibitors given its key role in a wide range of biological processes including the generation of antibody diversity, DNA replication in a number of viruses, and the formation of DNA strand breaks during anticancer drug therapy. To accelerate the discovery of inhibitors of UNG we have developed a uracil-directed ligand tethering strategy. In this efficient approach, a uracil aldehyde ligand is tethered via alkyloxyamine linker chemistry to a diverse array of aldehyde binding elements. Thus, the mechanism of extrahelical recognition of the uracil ligand is exploited to target the UNG active site, and alkyloxyamine linker tethering is used to randomly explore peripheral binding pockets. Since no compound purification is required, this approach rapidly identified the first small-molecule inhibitors of human UNG with micromolar to submicromolar binding affinities. In a surprising result, these uracil-based ligands are found not only to bind to the active site but also to bind to a second uncompetitive site. The weaker uncompetitive site suggests the existence of a transient binding site for uracil during the multistep extrahelical recognition mechanism. This very general inhibitor design strategy can be easily adapted to target other enzymes that recognize nucleobases, including other DNA repair enzymes that recognize other types of extrahelical DNA bases.