8-bromooctyl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside | 382607-65-0

• 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: 8-bromooctyl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside
• 英文别名: [(2R,3R,4S,5R,6R)-3,4,5-tribenzoyloxy-6-(8-bromooctoxy)oxan-2-yl]methyl benzoate
• CAS: 382607-65-0
• 化学式: C₄₂H₄₃BrO₁₀
• 分子量: 787.701
• InChiKey: VBFBHMHPVXNLJH-XBQZPALJSA-N

物化性质

• 沸点：
  818.6±65.0 °C(predicted)
• 密度：
  1.35±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9.6
• 重原子数：
  53
• 可旋转键数：
  22
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  124
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  8-bromooctyl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside 在 4 A molecular sieve 、 sodium methylate 、 lithium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 2-amino-6-(3-iodobenzyloxy)-9-(octyl-β-D-glucopyranoside)purine
  参考文献：
  名称：

  Synthesis of ¹³¹I-Labeled Glucose-Conjugated Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

  摘要：

  O-6-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C-8-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O-6-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O-6-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC50 values) of 0.8 and 0.45 mu M for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the I-131-(hetero)arylmethylene group at the O-6-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [I-131]I- were performed with radiochemical yields of > 70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [I-131]ITGG, [(131)]IBGG, [I-131]ITG, and [I-131]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [I-131]IBG and [I-131]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.

  DOI：

  10.1021/jm050588q
• 作为产物：
  描述：

  2,3,4,6-tetra-O-benzoylglucosyl bromide 在 三氟化硼乙醚 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 sodium iodide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 86.0h， 生成 8-bromooctyl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside
  参考文献：
  名称：

  Synthesis of ¹³¹I-Labeled Glucose-Conjugated Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

  摘要：

  O-6-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C-8-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O-6-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O-6-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC50 values) of 0.8 and 0.45 mu M for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the I-131-(hetero)arylmethylene group at the O-6-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [I-131]I- were performed with radiochemical yields of > 70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [I-131]ITGG, [(131)]IBGG, [I-131]ITG, and [I-131]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [I-131]IBG and [I-131]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.

  DOI：

  10.1021/jm050588q

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.
• Synthesis of 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-β-d-glucosyl)-purine: a novel radioligand for positron emission tomography studies of the O6-methylguanine-DNA methyltransferase (MGMT) status of tumour tissue
  作者：Ralf Schirrmacher、Ute Mühlhausen、Björn Wängler、Esther Schirrmacher、Jost Reinhard、Gerd Nagel、Bernd Kaina、Markus Piel、Manfred Wießler、Frank Rösch

  DOI：10.1016/s0040-4039(02)01394-1

  日期：2002.9

  The synthesis of the novel glucose conjugated O-6-methylguanine-DNA methyltransferase (MGMT) inhibitor 2-amino-6-(2-[F-18]fluoro-pyridine-4-ylmethoxy)-9-(octyl-alpha-D-glucosyl)-purine is reported. This compound might serve as a radiotracer for the determination of the MGMT status of tumour tissue. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Synthesis of ¹³¹I-Labeled Glucose-Conjugated Inhibitors of <i>O</i>⁶-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging
  作者：Ute Mühlhausen、Ralf Schirrmacher、Markus Piel、Bernd Lecher、Manuela Briegert、Andrea Piee-Staffa、Bernd Kaina、Frank Rösch

  DOI：10.1021/jm050588q

  日期：2006.1.1

  O-6-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C-8-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O-6-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O-6-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC50 values) of 0.8 and 0.45 mu M for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the I-131-(hetero)arylmethylene group at the O-6-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [I-131]I- were performed with radiochemical yields of > 70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [I-131]ITGG, [(131)]IBGG, [I-131]ITG, and [I-131]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [I-131]IBG and [I-131]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.