1-(甲基-丙-2-基氧基磷酰)氧基-4-硝基苯 | 3735-97-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 1-(甲基-丙-2-基氧基磷酰)氧基-4-硝基苯
• 中文别名: 异丙基(4-硝基苯基)甲基膦酸酯
• 英文名称: 4-nitrophenyl propan-2-yl methylphosphonate
• 英文别名: O-isopropyl p-nitrophenyl methylphosphonate；2-Propyl 4-nitrophenyl methyl phosphonate；4-nitrophenyl isopropyl methylphosphonate；isopropyl 4-nitrophenyl methylphosphonate；isopropyl p-nitrophenyl methylphosphonate；4-nitrophenyl 2-propyl methylphosphonate；4-Nitrophenyl 2-propylmethylphosphonate；1-[methyl(propan-2-yloxy)phosphoryl]oxy-4-nitrobenzene
• CAS: 3735-97-5
• 化学式: C₁₀H₁₄NO₅P
• 分子量: 259.199
• InChiKey: YSHVIWJFWCEDSQ-UHFFFAOYSA-N

物化性质

• 沸点：
  136 °C(Press: 0.40 Torr)
• 密度：
  1.260±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  81.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(甲基-丙-2-基氧基磷酰)氧基-4-硝基苯 在 Rsp₃₆₉₀ from Rhodobacter sphaeroides 作用下， 以 二甲基亚砜 为溶剂， 生成 对硝基苯酚
  参考文献：
  名称：

  Structural Characterization and Function Determination of a Nonspecific Carboxylate Esterase from the Amidohydrolase Superfamily with a Promiscuous Ability To Hydrolyze Methylphosphonate Esters

  摘要：

  The uncharacterized protein Rsp3690 from Rhodobacter sphaeroides is a member of the amidohydrolase superfamily of enzymes. In this investigation the gene for Rsp3690 was expressed in Escherichia coli and purified to homogeneity, and the three-dimensional structure was determined to a resolution of 1.8 angstrom. The protein folds as a distorted (beta/alpha)(8)-barrel, and the subunits associate as a homotetramer. The active site is localized to the C-terminal end of the beta-barrel and is highlighted by the formation of a binuclear metal center with two manganese ions that are bridged by Glu-175 and hydroxide. The remaining ligands to the metal center include His-32, His-34, His-207, His-236, and Asp-302. Rsp3690 was shown to catalyze the hydrolysis of a wide variety of carboxylate esters, in addition to organophosphate and organophosphonate esters. The best carboxylate ester substrates identified for Rsp3690 included 2-naphthyl acetate (k(cat)/K-m = 1.0 x 10(5) M-1 s(-1)), 2-naphthyl propionate (k(cat)/K-m = 1.5 x 10(5) M-1 s(-1)), 1-naphthyl acetate (k(cat)/K-m = 7.5 x 10(3) M-1 s(-1)), 4-methylumbelliferyl acetate (k(cat)/K-m = 2.7 x 10(3) M-1 s(-1)), 4-nitrophenyl acetate (k(cat)/K-m = 2.3 x 10(5) M-1 s(-1)), and 4-nitrophenyl butyrate (k(cat)/K-m = 8.8 x 10(5) M-1 s(-1)). The best organophosphonate ester substrates included ethyl 4-nitrophenyl methylphosphonate (k(cat)/K-m = 3.8 x 10(5) M-1 s(-1)) and isobutyl 4-nitrophenyl methylphosphonate (k(cat)/K-m = 1.1 x 10(4) M-1 s(-1)). The (S-p)-enantiomer of isobutyl 4-nitrophenyl methylphosphonate was hydrolyzed 10 times faster than the less toxic (R-p)-enantiomer. The high inherent catalytic activity of Rsp3690 for the hydrolysis of the toxic enantiomer of methylphosphonate esters make this enzyme an attractive target for directed evolution investigations.

  DOI：

  10.1021/bi5004266
• 作为产物：
  描述：

  4-nitrophenol sodium salt 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 生成 1-(甲基-丙-2-基氧基磷酰)氧基-4-硝基苯
  参考文献：
  名称：

  1,8-Diazabicyclo[5.4.0]undecene Mediated Transesterification ofp-Nitrophenyl Phosphonates: A Novel Route to Phosphono Esters

  摘要：

  研究发现 DBU（1,8-二氮杂双环[5.4.0]十一烯）能有效地介导对硝基苯（PNP）膦酸盐与各种醇的酯交换反应。在 DBU 的存在下，使用伯醇、仲醇、酚和胺对双-PNP 膦酸盐进行反应，反应速度快，产率高，可得到相应的单烷基/芳基单-PNP 膦酸盐作为唯一产物（1，方案 2）。生成的单烷基/芳基单-PNP 膦酸盐可进一步与第二种醇反应，得到相应的不同二取代膦酸盐 3，或选择性水解，得到单烷基/芳基膦酸 2。我们将这种化学方法应用于制备一系列膦酸酯过渡态类似物 11a-e（方案 3），这些类似物可用作催化抗体的触价物。

  DOI：

  10.1055/s-1993-25982

文献信息

• Molecular Engineering of Organophosphate Hydrolysis Activity from a Weak Promiscuous Lactonase Template
  作者：Monika M. Meier、Chitra Rajendran、Christoph Malisi、Nicholas G. Fox、Chengfu Xu、Sandra Schlee、David P. Barondeau、Birte Höcker、Reinhard Sterner、Frank M. Raushel

  DOI：10.1021/ja405911h

  日期：2013.8.7

  lactonase (PLL) family that show promiscuous organophosphate-degrading activity. Starting from a weakly promiscuous PLL scaffold (Dr0930 from Deinococcus radiodurans ), we designed an extremely efficient organophosphate hydrolase (OPH) with broad substrate specificity using rational and random mutagenesis in combination with in vitro activity screening. The OPH activity for seven organophosphate substrates

  酶的快速进化为蛋白质非凡的适应性提供了独特的分子见解，并有助于阐明氨基酸序列、结构和功能之间的关系。我们研究了来自 Pseudomonas diminuta (PdPTE) 的磷酸三酯酶的进化，该酶以显着的催化效率水解合成有机磷酸酯。PTE 被认为是一种进化上“年轻”的酶，据推测它是从磷酸三酯酶样内酯酶 (PLL) 家族的成员进化而来的，这些成员表现出混杂的有机磷降解活性。从弱混杂的 PLL 支架（来自耐辐射奇异球菌的 Dr0930）开始，我们使用合理和随机诱变结合体外活性筛选设计了一种具有广泛底物特异性的极其有效的有机磷酸酯水解酶 (OPH)。七个有机磷底物的 OPH 活性同时增强了多达 5 个数量级，实现了高达 10(6) M(-1) s(-1) 的催化效率的绝对值。结构和计算分析确定了工程化 PLL 变体增强 OPH 活性的分子基础，并证明 PdPTE 和工程化 PLL 中的 OPH
• Substrate Analogues for the Enzyme-Catalyzed Detoxification of the Organophosphate Nerve Agents—Sarin, Soman, and Cyclosarin
  作者：Andrew N. Bigley、Steven P. Harvey、Tamari Narindoshvili、Frank M. Raushel

  DOI：10.1021/acs.biochem.1c00361

  日期：2021.9.28

  The G-type nerve agents, sarin (GB), soman (GD), and cyclosarin (GF), are among the most toxic compounds known. Much progress has been made in evolving the enzyme phosphotriesterase (PTE) from Pseudomonas diminuta for the decontamination of the G-agents; however, the extreme toxicity of the G-agents makes the use of substrate analogues necessary. Typical analogues utilize a chromogenic leaving group to facilitate high-throughput screening, and substitution of an O-methyl for the P-methyl group found in the G-agents, in an effort to reduce toxicity. Till date, there has been no systematic evaluation of the effects of these substitutions on catalytic activity, and the presumed reduction in toxicity has not been tested. A series of 21 G-agent analogues, including all combinations of O-methyl, p-nitrophenyl, and thiophosphate substitutions, have been synthesized and evaluated for their ability to unveil the stereoselectivity and catalytic activity of PTE variants against the authentic G-type nerve agents. The potential toxicity of these analogues was evaluated by measuring the rate of inactivation of acetylcholinesterase (AChE). All of the substitutions reduced inactivation of AChE by more than 100-fold, with the most effective being the thiophosphate analogues, which reduced the rate of inactivation by about 4–5 orders of magnitude. The analogues were found to reliably predict changes in catalytic activity and stereoselectivity of the PTE variants and led to the identification of the BHR-30 variant, which has no apparent stereoselectivity against GD and a kcat/Km of 1.4 × 106, making it the most efficient enzyme for GD decontamination reported till date.

  G型神经毒剂，包括沙林（GB）、梭曼（GD）和环沙林（GF），是已知毒性最强的化合物之一。在利用铜绿假单胞菌的磷酸三酯酶（PTE）进化以去除G型毒剂方面已经取得了很大进展；然而，G型毒剂的极高毒性使得使用底物类似物成为必要。典型的类似物采用色原性离去基团以促进高通量筛选，并通过用O-甲基取代G型毒剂中的P-甲基，以期降低毒性。迄今为止，尚未对这些取代基对催化活性的影响进行系统评估，并且所推测的毒性降低尚未得到验证。合成了一系列21种G型毒剂类似物，包括所有O-甲基、对硝基苯基和硫代磷酸酯取代基的组合，并评估了它们揭示PTE变体对实际G型神经毒剂的立体选择性和催化活性的能力。通过测定乙酰胆碱酯酶（AChE）的失活速率，评估了这些类似物的潜在毒性。所有取代基使AChE失活减缓了100倍以上，其中最有效的是硫代磷酸酯类似物，其使失活速率降低了约4-5个数量级。发现这些类似物可准确预测催化活性和立体选择性的变化，并有助于鉴定出BHR-30变体，该变体对GD没有明显的立体选择性，且kcat/Km值为1.4 × 106，使其成为迄今为止报道的用于GD去除的最有效的酶。
• New Safe Method for Preparation of Sarin-Exposed Human Erythrocytes Acetylcholinesterase Using Non-Toxic and Stable Sarin Analogue Isopropyl p-Nitrophenyl Methylphosphonate and its Application to Evaluation of Nerve Agent Antidotes
  作者：Hikoto Ohta、Takeshi Ohmori、Shinichi Suzuki、Hiroshi Ikegaya、Koichi Sakurada、Takehiko Takatori

  DOI：10.1007/s11095-006-9123-1

  日期：2006.12

  A non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was synthesized for safe preparation of sarin-exposed acetylcholinesterase (AChE). This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory concentration (IC50) on 0.04 U/ml human erythrocytes AChE was 15 nM. This reagent was thought to be especially useful since it enables experiments that require sarin-inhibited AChE, such as the development of antidotes for sarin, in a usual laboratory. To demonstrate the usefulness of this method, 40 known and novel pyridinealdoxime methiodide (PAM)-type oxime antidotes were synthesized, and their reactivation activities to INMP-exposed AChE and structure–activities correlation were studied. Among the antidotes tested in this experiment except for 2-PAM, the compound found to have the highest reactivation activity, was the novel hydrophobic 2-PAM-type compound, 2-[(hydroxyimino)methyl]-1-[4-(tert-butyl)benzyl] pyridinium bromide.

  一种无毒且稳定的沙林类似物异丙基对硝基苯基甲基磷酸酯(INMP)被合成，用于安全制备沙林暴露的乙酰胆碱酯酶(AChE)。该试剂在数年内保持稳定，可以在普通实验室中处理，无需特殊护理，其对0.04 U/ml人类红细胞AChE的50%抑制浓度(IC50)为15 nM。该试剂被认为特别有用，因为它能够在普通实验室中进行需要沙林抑制AChE的实验，例如沙林解毒剂的开发。为了证明该方法的有效性，合成了40种已知和新型的吡啶醛肟(潘)类解毒剂，并研究了它们对INMP暴露的AChE的再活化活性及其结构–活性相关性。在此次实验中测试的解毒剂中，除了2-PAM外，发现具有最高再活化活性的化合物是一种新型的疏水性2-PAM类化合物，即2-[(羟亚胺)甲基]-1-[4-(叔丁基)苯基]吡啶溴化物。
• Cholinesterase Inhibitors
  申请人：Thompson Charles M.

  公开号：US20130343994A1

  公开（公告）日：2013-12-26

  The invention provides compounds that inhibit cholinesterases, such as acetylcholinesterase and butyrylcholinesterase. Such compounds are useful to prevent or treat exposure of a patient (e.g., a human) to an organophosphoric nerve agent (e.g., sarin and VX) or to treat a patient suffering from a neurodegenerative disorder such as Alzheimer's Disease or Lewy Body Dementia. The compounds are further useful as diagnostic tools for use in medical or research radiography (e.g., positron emission tomography) when synthesized with a radionuclide (e.g., [18F]. Synthetic schemes to produce such compounds are also provided.

  该发明提供了抑制胆碱酯酶的化合物，例如乙酰胆碱酯酶和丁酰胆碱酯酶。这些化合物可用于预防或治疗患者（例如人类）暴露于有机磷神经毒剂（例如沙林和VX）或治疗患有神经退行性疾病（如阿尔茨海默病或路易体痴呆症）的患者。这些化合物还可作为诊断工具用于医学或研究放射学（例如正电子发射断层扫描）时，当与放射性核素（例如[18F]）合成时。还提供了用于合成这些化合物的合成方案。
• COMPOUNDS FOR CENTRAL REACTIVATION OF ORGANOPHOSPHORUS- BASED COMPOUND-INHIBITED ACETYLCHOLINESTERASE AND/OR INACTIVATION OF ORGANOPHOSPHORUS-BASED ACETYLCHOLINESTERASE INHIBITORS AND RELATED COMPOSITIONS METHODS AND SYSTEMS FOR MAKING AND USING THEM
  申请人：LAWRENCE LIVERMORE NATIONAL SECURITY, LLC

  公开号：US20190152920A1

  公开（公告）日：2019-05-23

  Described herein are oxime compounds capable of inactivating OP-based AChE inhibitors, crossing the blood brain barrier (BBB), and/or reactivation of OP-inhibited acetylcholinesterase (AChE) and related methods, systems and compositions for inactivation of one or more OP-based AChE inhibitors, therapeutic and/or prophylactic treatment of an individual, and/or decomposition of OP-based AChE inhibitors for decontamination.

  本文描述了一种肟类化合物，能够失活OP类AChE抑制剂，穿过血脑屏障（BBB），重新激活OP抑制的乙酰胆碱酯酶（AChE）以及相关方法、系统和组合物，用于失活一个或多个OP类AChE抑制剂，治疗和/或预防个体，以及分解OP类AChE抑制剂以进行去污。