[(2R,3S,4R,5S)-5-acetamido-2,3,4,6-tetrahydroxy-hexyl] dihydrogen phosphate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [(2R,3S,4R,5S)-5-acetamido-2,3,4,6-tetrahydroxy-hexyl] dihydrogen phosphate
• 英文别名: [(2R,3S,4R,5S)-5-acetamido-2,3,4,6-tetrahydroxyhexyl] dihydrogen phosphate
• 化学式: C₈H₁₈NO₉P
• 分子量: 303.206
• InChiKey: WHHOIWRDVIBHSP-LXGUWJNJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  177
• 氢给体数：
  7
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  D-氨基葡萄糖6-磷酸 在 sodium hydroxide 、 sodium tetrahydroborate 作用下， 以 水 为溶剂， 反应 3.0h， 生成 [(2R,3S,4R,5S)-5-acetamido-2,3,4,6-tetrahydroxy-hexyl] dihydrogen phosphate
  参考文献：
  名称：

  Hydrophobic derivatives of 2-amino-2-deoxy-d-glucitol-6-phosphate: A new type of d-Glucosamine-6-phosphate synthase inhibitors with antifungal action

  摘要：

  Several N-acyl and ester derivatives of 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) have been synthesised and tested as inhibitors of fungal enzymes involved in early steps of chitin biosynthesis and for antifungal activity. All the tested derivatives were found to be much poorer inhibitors of the enzyme, D-glucosamine-6-phosphate (GIcN-6-P) synthase, than the parent compound but some of them exhibited much better antifungal activity. MIC values for the investigated compounds ranged between 10 mg mL(-1), found for ADGP and 0.3 mg mL(-1) for the most active derivative, namely ADGP dimethyl ester. Increased affinity of ADGP derivatives to the artificial immobilised cell membrane was correlated with their enhanced ability to be taken up by fungal cells by free diffusion. It was found that some of the examined derivatives behaved as 'pro-drugs' and after internalisation were converted into ADGP in the cell-free extract. This conversion was relatively rapid for ADGP esters but very slow for N-acyl derivatives. Results of our studies demonstrate a possibility of design and preparation of GIcN-6-P synthase inhibitors exhibiting antifungal activity. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00049-x

文献信息

• Structure of MurNAc 6-Phosphate Hydrolase (MurQ) from <i>Haemophilus influenzae</i> with a Bound Inhibitor
  作者：Timin Hadi、Saugata Hazra、Martin E. Tanner、John S. Blanchard

  DOI：10.1021/bi4010446

  日期：2013.12.23

  The breakdown and recycling of peptidoglycan, an essential polymeric cell structure, occur in a number of bacterial species. A key enzyme in the recycling pathway of one of the components of the peptidoglycan layer, N-acetylmuramic acid (MurNAc), is MurNAc 6-phosphate hydrolase (MurQ). This enzyme catalyzes the cofactor-independent cleavage of a relatively nonlabile ether bond and presents an interesting target for mechanistic studies. Open chain product and substrate analogues were synthesized and tested as competitive inhibitors (K,, values of 1.1 +/- 0.3 and 0.23 +/- 0.02 mM, respectively) of the MurNAc 6P hydrolase from Escherichia coli (MurQ-EC). To identify the roles of active site residues that are important for catalysis, the substrate analogue was cocrystallized with the MurNAc 6P hydrolase from Haemophilus influenzae (MurQ-HI) that was amenable to crystallographic studies. The cocrystal structure of MurQ-HI with the substrate analogue showed that Glu89 was located in the proximity of both the C2 atom and the oxygen at the C3 position of the bound inhibitor and that no other potential acid/base residue that could act as an active site acid/base was located in the vicinity. The conserved residues Glu120 and Lys239 were found within hydrogen bonding distance of the CS hydroxyl group and C6 phosphate group, suggesting that they play a role in substrate binding and ring opening. Combining these results with previous biochemical data, we propose a one-base mechanism of action in which Glu89 functions to both deprotonate at the C2 position and assist in the departure of the lactyl ether at the C3 position. This same residue would serve to deprotonate the incoming water and reprotonate the enolate in the second half of the catalytic cycle.
• Hydrophobic derivatives of 2-amino-2-deoxy-d-glucitol-6-phosphate: A new type of d-Glucosamine-6-phosphate synthase inhibitors with antifungal action
  作者：Agnieszka M Janiak、Maria Hoffmann、Maria J Milewska、Sławomir Milewski

  DOI：10.1016/s0968-0896(03)00049-x

  日期：2003.4

  Several N-acyl and ester derivatives of 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) have been synthesised and tested as inhibitors of fungal enzymes involved in early steps of chitin biosynthesis and for antifungal activity. All the tested derivatives were found to be much poorer inhibitors of the enzyme, D-glucosamine-6-phosphate (GIcN-6-P) synthase, than the parent compound but some of them exhibited much better antifungal activity. MIC values for the investigated compounds ranged between 10 mg mL(-1), found for ADGP and 0.3 mg mL(-1) for the most active derivative, namely ADGP dimethyl ester. Increased affinity of ADGP derivatives to the artificial immobilised cell membrane was correlated with their enhanced ability to be taken up by fungal cells by free diffusion. It was found that some of the examined derivatives behaved as 'pro-drugs' and after internalisation were converted into ADGP in the cell-free extract. This conversion was relatively rapid for ADGP esters but very slow for N-acyl derivatives. Results of our studies demonstrate a possibility of design and preparation of GIcN-6-P synthase inhibitors exhibiting antifungal activity. (C) 2003 Elsevier Science Ltd. All rights reserved.