4-{(diethoxyphosphoryl)(difluoro)methyl}benzyl dibromide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: 4-{(diethoxyphosphoryl)(difluoro)methyl}benzyl dibromide
• 英文别名: 1-(Dibromomethyl)-4-[diethoxyphosphoryl(difluoro)methyl]benzene
• 化学式: C₁₂H₁₅Br₂F₂O₃P
• 分子量: 436.028
• InChiKey: SNBFRRLZHXCYJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  溴氟甲基膦酸二乙酯 在 N-溴代丁二酰亚胺(NBS) 、 镉 作用下， 以 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 17.5h， 生成 4-{(diethoxyphosphoryl)(difluoro)methyl}benzyl dibromide
  参考文献：
  名称：

  Structure of Protein Tyrosine Phosphatase 1B in Complex with Inhibitors Bearing Two Phosphotyrosine Mimetics

  摘要：

  Protein tyrosine phosphatases (PTPases) are signal-transducing enzymes that dephosphorylate intracellular proteins that have phosphorylated tyrosine residues. It has been demonstrated that protein tyrosine phosphatase 1B (PTP1B) is an attractive therapeutic target because of its involvement in regulating insulin sensitivity (Elcheby et al. Science 1999,283, 1544-1548). The identification of a second binding site in PTP1B (Puius et al., Proc. Natl. Acad. Sci. U.S.A 1997, 94, 13420-13425) suggests a new strategy for inhibitor design, where appropriate compounds may be made to simultaneously occupy both binding sites to gain much higher affinity and selectivity. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have determined the crystal structure of PTP1B complexed with two non-peptidyl inhibitors, 4 and 5, both of which contain two aryl difluoromethylenephosphonic acid groups, a nonhydrolyzable phosphate mimetic. The structures were determined and refined to 2.35 and 2.50 Angstrom resolution, respectively. Although one of the inhibitors seems to have satisfied the perceived requirement for dual binding, it did not bind both the active site and the adjacent noncatalytic binding site as expected. The second or distal phosphonate group instead extends into the solvent and makes water-mediated interactions with Arg-47. The selectivity of the more potent of these two inhibitors, as well as four other inhibitors bearing two such phosphate mimetics for PTP1B versus seven other PTPases, was examined, In general, selectivity was modest to good when compared to PTPases Cdc25a, PTPmeg-1, PTP beta, and CD45. However, selectivity was generally poor when compared to other PTPases such as SHP-1, SHP-2, and especially TCPTP, for which almost no selectivity was found. The implications these results have concerning the utility of dual-binding inhibitors are discussed.

  DOI：

  10.1021/jm010266w

文献信息

• Enzymatic desymmetrization of prochiral 2-benzyl-1,3-propanediol derivatives: A practical chemoenzymatic synthesis of novel phosphorylated tyrosine analogues
  作者：Tsutomu Yokomatsu、Takayuki Minowa、Tetsuo Murano、Shiroshi Shibuya

  DOI：10.1016/s0040-4020(98)00586-9

  日期：1998.8

  (Phosphonomethyl)phenylalanine (Pmp) and (phosphonodifluoromethyl)phenylalanine (F(2)Pmp) as well as their beta-amino acid congeners were prepared as a protecting variant amenable to the peptide synthesis from readily available 2-benzyl-1,3-propandiols possessing either a diethylphosphonomethyl- or diethylphosphonodifluoromethyl functionality at the para-position via the lipase-catalyzed desymmetrization. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Rational Design of Selective Organoruthenium Inhibitors of Protein Tyrosine Phosphatase 1B
  作者：Jun Xiang Ong、Chun Wei Yap、Wee Han Ang

  DOI：10.1021/ic301884j

  日期：2012.11.19

  Protein tyrosine phosphatases (PTPs) belong to a large family of important regulatory enzymes involved in vital mammalian signaling pathways. Selective inhibitors of PTPs are highly valuable from a therapeutic standpoint given their association with various pathological conditions. One such target is PTP-1B which has previously been linked to diabetes and cancer. However, developing a selective inhibitor against PTP-1B has proven to be daunting because the enzyme shares a high degree of structural homology with TC-PTP, an essential PTP involved in modulating immune functions. To address this challenge, a series of organoruthenium complexes was developed to bind at the PTP substrate-binding site while simultaneously target the peripheral structural space. By capitalizing on the potential difference in the structural environment proximal to the active site between different PTPs, selectivity toward PTP-1B over TC-PTP was improved, paving the way for organoruthenium complexes as selective PTP-1B metalloinhibitors.
• Structure of Protein Tyrosine Phosphatase 1B in Complex with Inhibitors Bearing Two Phosphotyrosine Mimetics
  作者：Zongchao Jia、Qilu Ye、A. Nicole Dinaut、Qingping Wang、Deena Waddleton、Paul Payette、Chidambaram Ramachandran、Brian Kennedy、Gabriel Hum、Scott D. Taylor

  DOI：10.1021/jm010266w

  日期：2001.12.1

  Protein tyrosine phosphatases (PTPases) are signal-transducing enzymes that dephosphorylate intracellular proteins that have phosphorylated tyrosine residues. It has been demonstrated that protein tyrosine phosphatase 1B (PTP1B) is an attractive therapeutic target because of its involvement in regulating insulin sensitivity (Elcheby et al. Science 1999,283, 1544-1548). The identification of a second binding site in PTP1B (Puius et al., Proc. Natl. Acad. Sci. U.S.A 1997, 94, 13420-13425) suggests a new strategy for inhibitor design, where appropriate compounds may be made to simultaneously occupy both binding sites to gain much higher affinity and selectivity. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have determined the crystal structure of PTP1B complexed with two non-peptidyl inhibitors, 4 and 5, both of which contain two aryl difluoromethylenephosphonic acid groups, a nonhydrolyzable phosphate mimetic. The structures were determined and refined to 2.35 and 2.50 Angstrom resolution, respectively. Although one of the inhibitors seems to have satisfied the perceived requirement for dual binding, it did not bind both the active site and the adjacent noncatalytic binding site as expected. The second or distal phosphonate group instead extends into the solvent and makes water-mediated interactions with Arg-47. The selectivity of the more potent of these two inhibitors, as well as four other inhibitors bearing two such phosphate mimetics for PTP1B versus seven other PTPases, was examined, In general, selectivity was modest to good when compared to PTPases Cdc25a, PTPmeg-1, PTP beta, and CD45. However, selectivity was generally poor when compared to other PTPases such as SHP-1, SHP-2, and especially TCPTP, for which almost no selectivity was found. The implications these results have concerning the utility of dual-binding inhibitors are discussed.