6-[O⁶-(4-bromothenyl)-guan-9-yl]-hexyl-β-D-glucoside

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 6-[O⁶-(4-bromothenyl)-guan-9-yl]-hexyl-β-D-glucoside
• 英文别名: (2R,3R,4S,5S,6R)-2-[6-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]hexoxy]-6-(hydroxymethyl)oxane-3,4,5-triol
• 化学式: C₂₂H₃₀BrN₅O₇S
• 分子量: 588.48
• InChiKey: ZMMBMLJGFSVJRG-YUZRNDJPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  207
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  罗米鲁曲 在 sodium methylate 、 lithium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 6-[O⁶-(4-bromothenyl)-guan-9-yl]-hexyl-β-D-glucoside
  参考文献：
  名称：

  Monosaccharide-Linked Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT):  Synthesis, Molecular Modeling, and Structure−Activity Relationships

  摘要：

  A series of potential inhibitors of the human DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, omega-[O-6-R-guan-9-yl]-(CH2)(n)-beta -d-glucosides with R = benzyl or 4-bromothenyl and omega = n = 2, 4, ... 12, were compared with the established inhibitors O-6 -benzylguanine (O-6-BG), 8-aza-O-6-benzylguanine (8-aza-BG), and O-6-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC50 values of 0.62, 0.038, and 0.009 muM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC50 of ca. 0.5 muM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC50 values of ca. 0.03 muM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: 1QNT). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.

  DOI：

  10.1021/jm010006e

文献信息

• Monosaccharide-Linked Inhibitors of <i>O</i>⁶-Methylguanine-DNA Methyltransferase (MGMT):  Synthesis, Molecular Modeling, and Structure−Activity Relationships
  作者：Jost Reinhard、William E. Hull、Claus-Wilhelm von der Lieth、Uta Eichhorn、Hans-Christian Kliem、Bernd Kaina、Manfred Wiessler

  DOI：10.1021/jm010006e

  日期：2001.11.1

  A series of potential inhibitors of the human DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, omega-[O-6-R-guan-9-yl]-(CH2)(n)-beta -d-glucosides with R = benzyl or 4-bromothenyl and omega = n = 2, 4, ... 12, were compared with the established inhibitors O-6 -benzylguanine (O-6-BG), 8-aza-O-6-benzylguanine (8-aza-BG), and O-6-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC50 values of 0.62, 0.038, and 0.009 muM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC50 of ca. 0.5 muM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC50 values of ca. 0.03 muM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: 1QNT). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.