1-[3'-C-(hydroxymethyl)-β-D-glucopyranosyl]5-fluorouracil | 1375074-67-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[3'-C-(hydroxymethyl)-β-D-glucopyranosyl]5-fluorouracil
• 英文别名: 5-Fluoro-1-[3-C-(Hydroxymethyl)-Beta-D-Glucopyranosyl]pyrimidine-2,4(1h,3h)-Dione；5-fluoro-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-4,6-bis(hydroxymethyl)oxan-2-yl]pyrimidine-2,4-dione
• CAS: 1375074-67-1
• 化学式: C₁₁H₁₅FN₂O₈
• 分子量: 322.247
• InChiKey: ASRLDHHNHXDEKP-RZBPYSQRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  160
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  在 吡啶 、 三氟甲磺酸三甲基硅酯 、 氨 、 水 作用下， 以 甲醇 为溶剂， 反应 2.5h， 生成 1-[3'-C-(hydroxymethyl)-β-D-glucopyranosyl]5-fluorouracil
  参考文献：
  名称：

  3′-Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why

  摘要：

  Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic agents. Structure‐based design pinpointed that the 3′‐position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme’s cofactor, pyridoxal 5′‐phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1‐(β‐d‐glucopyranosyl)5‐fluorouracil (GlcFU) and its 3′‐CH2OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with Ki values of 7.9 and 27.1 μm, respectively. X‐ray crystallography revealed that the 3′‐CH2OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP γ‐phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking Quantum Mechanics/Molecular Mechanics – Poisson–Boltzmann Surface Area (QM/MM‐PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM‐PBSA revealed that the desolvation energy cost for binding of the 3′‐CH2OH‐substituted glucopyranose derivative out‐weigh the enthalpy gains from the extra contacts formed. The benefits of performing postdocking calculations employing a more accurate solvation model and the QM/MM‐PBSA methodology in lead optimization are therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant.

  DOI：

  10.1111/j.1747-0285.2012.01349.x