6-((bis-(tert-butyl))phosphono-difluoromethyl)-2-naphthoic acid | 219316-47-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-((bis-(tert-butyl))phosphono-difluoromethyl)-2-naphthoic acid
• 英文别名: 6-[[Bis[(2-methylpropan-2-yl)oxy]-oxidophosphaniumyl]-difluoromethyl]naphthalene-2-carboxylic acid；6-[[bis[(2-methylpropan-2-yl)oxy]-oxidophosphaniumyl]-difluoromethyl]naphthalene-2-carboxylic acid
• CAS: 219316-47-9
• 化学式: C₂₀H₂₅F₂O₅P
• 分子量: 414.386
• InChiKey: ZJWBGVVSJSAXAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  78.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-((bis-(tert-butyl))phosphono-difluoromethyl)-2-naphthoic acid 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 生成 [(6-Benzenesulfonylaminocarbonyl-naphthalen-2-yl)-difluoro-methyl]-phosphonic acid
  参考文献：
  名称：

  Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration

  摘要：

  Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00635-8
• 作为产物：
  描述：

  6-[(Di-tert-butoxy-phosphoryl)-difluoro-methyl]-naphthalene-2-carboxylic acid benzyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 3.5h， 以74%的产率得到6-((bis-(tert-butyl))phosphono-difluoromethyl)-2-naphthoic acid
  参考文献：
  名称：

  Structure-based design and synthesis of small molecule protein–tyrosine phosphatase 1B inhibitors

  摘要：

  Protein-tyrosine phosphatase (PTP) inhibitors are attractive as potential signal transduction-directed therapeutics which may be useful in the treatment of a variety of diseases. We have previously reported the X-ray structure of 1,1-difluoro-1-(2-naphthalenyl)methyl] phosphonic acid (4) complexed with the human the protein-tyrosine phosphatase 1B (PTP1B) and its use in the design of an analogue which binds with higher affinity within the catalytic site (Burke, T. R., Jr. et al. Biochemistry 1996, 35, 15989). In the current study, new naphthyldifluoromethyl phosphonic acids were designed bearing acidic functionality intended to interact with the PTP1B Arg47, which is situated just outside the catalytic pocket. This residue has been shown previously to provide key interactions with acidic residues of phosphotyrosyl-containing peptide substrates. Consistent with trends predicted by molecular dynamics calculations, the new analogues bound with 7- to 14-fold higher affinity than the parent 4, in principal validating the design rationale. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00140-0

文献信息

• Structure-based design and synthesis of small molecule protein–tyrosine phosphatase 1B inhibitors
  作者：Zhu-Jun Yao、Bin Ye、Xiong-Wu Wu、Shaomeng Wang、Li Wu、Zhong-Yin Zhang、Terrence R. Burke

  DOI：10.1016/s0968-0896(98)00140-0

  日期：1998.10

  Protein-tyrosine phosphatase (PTP) inhibitors are attractive as potential signal transduction-directed therapeutics which may be useful in the treatment of a variety of diseases. We have previously reported the X-ray structure of 1,1-difluoro-1-(2-naphthalenyl)methyl] phosphonic acid (4) complexed with the human the protein-tyrosine phosphatase 1B (PTP1B) and its use in the design of an analogue which binds with higher affinity within the catalytic site (Burke, T. R., Jr. et al. Biochemistry 1996, 35, 15989). In the current study, new naphthyldifluoromethyl phosphonic acids were designed bearing acidic functionality intended to interact with the PTP1B Arg47, which is situated just outside the catalytic pocket. This residue has been shown previously to provide key interactions with acidic residues of phosphotyrosyl-containing peptide substrates. Consistent with trends predicted by molecular dynamics calculations, the new analogues bound with 7- to 14-fold higher affinity than the parent 4, in principal validating the design rationale. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration
  作者：Ding-Guo Liu、Yang Gao、Johannes H. Voigt、Kyeong Lee、Marc C. Nicklaus、Li Wu、Zhong-Yin Zhang、Terrence R. Burke

  DOI：10.1016/s0960-894x(03)00635-8

  日期：2003.9

  Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors. (C) 2003 Elsevier Ltd. All rights reserved.