({3-Hydroxy-2-Oxo-4-[2-(Phosphonooxy)ethyl]pyridin-1(2h)-Yl}methyl)phosphonic Acid | 1326780-04-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ({3-Hydroxy-2-Oxo-4-[2-(Phosphonooxy)ethyl]pyridin-1(2h)-Yl}methyl)phosphonic Acid
• 英文别名: [3-hydroxy-2-oxo-4-(2-phosphonooxyethyl)pyridin-1-yl]methylphosphonic acid
• CAS: 1326780-04-4
• 化学式: C₈H₁₃NO₉P₂
• 分子量: 329.14
• InChiKey: RMAJJEZWSTVCSS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.5
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  165
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-氯-3-(甲氧基甲氧基)吡啶 在 四氮唑 、 三甲基溴硅烷 、 palladium on activated charcoal 、 氢气 、 叔丁基锂 、 sodium hydride 、 potassium carbonate 、 间氯过氧苯甲酸 作用下， 以 乙腈 为溶剂， 生成 ({3-Hydroxy-2-Oxo-4-[2-(Phosphonooxy)ethyl]pyridin-1(2h)-Yl}methyl)phosphonic Acid
  参考文献：
  名称：

  Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase

  摘要：

  Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K-i = 14 mu M) that is comparable to that of FBP (K-m = 2 mu m) or its inert analog TBP (K-i = 1 mu M). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 angstrom) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn2+. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn2+ are not consistent with a strong interaction. To determine if Zn2+ coordination occurs in the GIFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn2+ coordination to binding of 8 to GlFBPA. (C) 2010 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.jinorgbio.2010.12.012

文献信息

• Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase
  作者：Zhimin Li、Zhengang Liu、Dae Won Cho、Jiwen Zou、Maozhen Gong、Robert M. Breece、Andrey Galkin、Ling Li、Hong Zhao、Gabriel D. Maestas、David L. Tierney、Osnat Herzberg、Debra Dunaway-Mariano、Patrick S. Mariano

  DOI：10.1016/j.jinorgbio.2010.12.012

  日期：2011.4

  Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K-i = 14 mu M) that is comparable to that of FBP (K-m = 2 mu m) or its inert analog TBP (K-i = 1 mu M). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 angstrom) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn2+. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn2+ are not consistent with a strong interaction. To determine if Zn2+ coordination occurs in the GIFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn2+ coordination to binding of 8 to GlFBPA. (C) 2010 Elsevier Inc. All rights reserved.