dihydroorotate | 14886-65-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: dihydroorotate
• 英文别名: DHO；6-carboxy-2-oxo-5,6-dihydro-1H-pyrimidin-4-olate
• CAS: 14886-65-8
• 化学式: C₅H₅N₂O₄
• 分子量: 157.106
• InChiKey: UFIVEPVSAGBUSI-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  98.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  dihydroorotate 在 recombinant wild type Toxoplasma gondii dihydroorotate dehydrogenase 、 potassium chloride 、 decylubiquinone 作用下， 以 乙醇 为溶剂， 生成 2,6-二氧代-3H-嘧啶-4-羧酸酯
  参考文献：
  名称：

  Identification of dihydroorotate dehydrogenase as a relevant drug target for 1-hydroxyquinolones in Toxoplasma gondii

  摘要：

  1-Hydroxyquinolones as for example 1-hydroxy-2-dodecyl-4(1)quinolone (HDQ) are effective growth inhibitors for Toxoplasma gondii. These compounds were shown to interfere with the respiratory chain function by inhibition of type II NADH dehydrogenase activity. With the aid of partial drug resistant mutants we identified in this study the fourth enzyme of the de nova pyrimidine synthesis pathway, the T. gondii dihydroorotate dehydrogenase (TgDHODH), as an additional 1-hydroxyquinolone target. A single point mutation was found in the TgDHODH coding sequence of drug resistant clones that change a conserved Asn into Ser in the vicinity of the dihydroorotate binding site. This mutation is sufficient to confer the partial drug resistance phenotype as shown by allele replacement. Enzyme kinetics revealed that 1-hydroxyquinolones inhibit wild type TgDHODH with IC(50)s in the nanomolar range, while the IC(50)s for the N302S mutant were significantly increased. Furthermore, inhibition kinetics revealed that 1-hydroxyquinolones act as competitive inhibitors for the electron acceptor Q(D), but as uncompetitive inhibitors for dihydroorotate. Moreover, heterologous expression of the ubiquinone independent DHODH from Saccharomyces cerevisiae in T. gondii also leads to partial 1-hydroxyquinolone resistance. Our data suggest that inhibition of TgDHODH activity significantly contributes to the growth inhibiting potential of 1-hydroxyquinolones in T. gondii. (C) 2013 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.molbiopara.2013.05.008

文献信息

• Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
  申请人：Leban Johan

  公开号：US20060199856A1

  公开（公告）日：2006-09-07

  The present invention relates to a novel compounds that can be used as anti-inflammatory, immunomodulatory and antiproliferatory agents. In particular, the invention refers to new compounds which inhibit dihydroorotate dehydrogenase (DHODH), a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehyrogenase (DHODH).

  本发明涉及一种新型化合物，可用作抗炎、免疫调节和抗增殖剂。具体而言，本发明涉及抑制二氢乳酸脱氢酶（DHODH）的新化合物，以及制造它们的方法、含有它们的制药组合物和它们在治疗和预防疾病方面的用途，特别是在抑制二氢乳酸脱氢酶（DHODH）具有优势的疾病中的使用。
• Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
  申请人：4SC AG

  公开号：US07423057B2

  公开（公告）日：2008-09-09

  The present invention relates to a novel compounds that can be used as anti-inflammatory, immunomodulatory and antiproliferatory agents. In particular, the invention refers to new compounds which inhibit dihydroorotate dehydrogenase (DHODH), a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehyrogenase (DHODH).

  本发明涉及一种新型化合物，可用作抗炎、免疫调节和抗增殖剂。具体而言，本发明涉及新型化合物，其抑制双氢乳酸酸脱氢酶（DHODH）的过程，以及制造这些化合物的方法，包含它们的制药组合物，以及它们用于治疗和预防疾病的用途，特别是在需要抑制双氢乳酸酸脱氢酶（DHODH）的疾病中的应用。
• Identification of dihydroorotate dehydrogenase as a relevant drug target for 1-hydroxyquinolones in Toxoplasma gondii
  作者：Jana Hegewald、Uwe Gross、Wolfgang Bohne

  DOI：10.1016/j.molbiopara.2013.05.008

  日期：2013.7

  1-Hydroxyquinolones as for example 1-hydroxy-2-dodecyl-4(1)quinolone (HDQ) are effective growth inhibitors for Toxoplasma gondii. These compounds were shown to interfere with the respiratory chain function by inhibition of type II NADH dehydrogenase activity. With the aid of partial drug resistant mutants we identified in this study the fourth enzyme of the de nova pyrimidine synthesis pathway, the T. gondii dihydroorotate dehydrogenase (TgDHODH), as an additional 1-hydroxyquinolone target. A single point mutation was found in the TgDHODH coding sequence of drug resistant clones that change a conserved Asn into Ser in the vicinity of the dihydroorotate binding site. This mutation is sufficient to confer the partial drug resistance phenotype as shown by allele replacement. Enzyme kinetics revealed that 1-hydroxyquinolones inhibit wild type TgDHODH with IC(50)s in the nanomolar range, while the IC(50)s for the N302S mutant were significantly increased. Furthermore, inhibition kinetics revealed that 1-hydroxyquinolones act as competitive inhibitors for the electron acceptor Q(D), but as uncompetitive inhibitors for dihydroorotate. Moreover, heterologous expression of the ubiquinone independent DHODH from Saccharomyces cerevisiae in T. gondii also leads to partial 1-hydroxyquinolone resistance. Our data suggest that inhibition of TgDHODH activity significantly contributes to the growth inhibiting potential of 1-hydroxyquinolones in T. gondii. (C) 2013 Elsevier B.V. All rights reserved.