benzyl 2-benzyloxycarbonylamino-4-(dihydroxyphosphoryl)butanoate | 926281-41-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: benzyl 2-benzyloxycarbonylamino-4-(dihydroxyphosphoryl)butanoate
• 英文别名: benzyl 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoate；[4-oxo-4-phenylmethoxy-3-(phenylmethoxycarbonylamino)butyl]phosphonic acid
• CAS: 926281-41-6
• 化学式: C₁₉H₂₂NO₇P
• 分子量: 407.36
• InChiKey: KSNCZXRLRAAAQD-UHFFFAOYSA-N

物化性质

• 熔点：
  101-103 °C
• 密度：
  1.354±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  benzyl 2-benzyloxycarbonylamino-4-(dihydroxyphosphoryl)butanoate 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 Butanoic acid,4-(dichlorophosphinyl)-2-[[(phenylmethoxy)carbonyl]amino]-,phenylmethyl ester
  参考文献：
  名称：

  有效和选择性的γ-谷氨酰转肽酶抑制剂GGsTop的改进合成及其潜在水解产物的抑制活性评估

  摘要：

  先前报道的合成方法可合成2-氨基-4-{[3-（羧甲基）苯氧基]（甲氧基）磷酸基}丁酸（GGsTop），这是一种有效，选择性高，无毒且不可逆的γ-谷氨酰转肽酶抑制剂（GGT）得到了显着改善。该路线分四个步骤提供了GGsTop，其价格便宜，起始原料的总产率为32％，即，相对于先前的方案，产率提高了大约六倍。GGsTop潜在水解产物的合成和抑制活性评估清楚地表明GGsTop是活性抑制剂，可以想到的水解产物几乎不影响人类GGT的活性。

  DOI：

  10.1016/j.tetlet.2017.08.019
• 作为产物：
  描述：

  2-(N-benzyloxycarbonylamino)-4-phosphonobutanoic acid monosodium salt 、 苯甲醇 在 氯化亚砜 作用下， 反应 20.25h， 以84%的产率得到benzyl 2-benzyloxycarbonylamino-4-(dihydroxyphosphoryl)butanoate
  参考文献：
  名称：

  PHOSPHONIC ACID DIESTER DERIVATIVE AND METHOD FOR PRODUCING THEREOF

  摘要：

  一个由下列一般公式（1）表示的膦酸二酯衍生物，其中R1和R2中至少有一个表示一个离去基团。

  公开号：

  US20090163725A1

文献信息

• Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of γ-glutamyl transpeptidase for probing cysteinyl-glycine binding site
  作者：Mado Nakajima、Bunta Watanabe、Liyou Han、Bun-ichi Shimizu、Kei Wada、Keiichi Fukuyama、Hideyuki Suzuki、Jun Hiratake

  DOI：10.1016/j.bmc.2013.12.034

  日期：2014.2

  and irreversibly by the peptidyl phosphorus esters with a good leaving group (phenoxide). Human GGT was highly selective for l-aliphatic amino acid such as l-2-aminobutyrate (l-Cys mimic) at the Cys binding site, whereas E. coli GGT significantly preferred l-Phe mimic at this site. The C-terminal Gly and a l-amino acid analogue at the Cys binding site were necessary for inhibition, suggesting that

  γ-谷氨酰转肽酶（GGT）催化谷胱甘肽及其S-缀合物的γ-谷氨酰键断裂，通过谷胱甘肽体内稳态参与许多生理和病理学过程。定义其Cys-Gly结合位点不仅在定义GGT的生理功能方面非常重要，而且在设计用于药物目的的特异性和有效抑制剂方面也非常重要。在这里，我们报告合成和评估一系列谷胱甘肽类似肽基磷酸酯作为人和大肠杆菌的基于机理的抑制剂用于探测Cys-Gly结合位点的结构和立体化学偏好的GGT。具有良好离去基团（酚盐）的肽基磷酸酯均强烈且不可逆地抑制了这两种酶。人类GGT是为高度选择性升-脂族氨基酸如升-2-氨基丁酸（升-Cys模拟物）在半胱氨酸结合位点，而大肠杆菌GGT显著优选升在此位点-Phe模拟物。C末端结合位点的C末端Gly和一个1-氨基酸类似物是抑制所必需的，这表明人GGT对谷胱甘肽（γ-Glu- 1 -Cys-Gly）具有高度选择性。GGT对谷胱甘肽没有选择性，但仍保留了二肽（1 -
• NAHLSGEN OPTICAL RESOLUTION METHOD
  申请人：KYOTO UNIVERSITY

  公开号：US20190225634A1

  公开（公告）日：2019-07-25

  Provided is a method for separating the four optical isomers of Nahlsgen. The method according to the present invention for producing a mixture of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate includes subjecting a mixture of the four optical isomers, represented by Formula (1′), to fractional crystallization from water or from a solvent mixture of water and a water-soluble organic solvent, to precipitate a mixture of a compound represented by Formula (1-1′-1) and a compound represented by Formula (1-4′-1), where Formulae (1′), (1-1′-1), and (1-4′-1) are expressed as follows:

  提供了一种分离Nahlsgen的四种光学异构体的方法。根据本发明的方法，用于产生一种D-2-氨基-4-[(Rp)-(3-羧甲基苯氧基)(甲氧基)磷酰基]丁酸水合物和一种L-2-氨基-4-[(Sp)-(3-羧甲基苯氧基)(甲氧基)磷酰基]丁酸水合物的混合物的方法包括将由式（1′）表示的四种光学异构体的混合物经过从水或水和水溶性有机溶剂的溶剂混合物中的分馏结晶，以沉淀出由式（1-1′-1）和式（1-4′-1）表示的化合物的混合物，其中式（1′）、（1-1′-1）和（1-4′-1）的式如下所示：
• Phosphonic acid diester derivative and method for producing thereof
  申请人：——

  公开号：US08129557B2

  公开（公告）日：2012-03-06

  A phosphonic acid diester derivative represented by the following general formula (1): wherein at least one of R1 and R2 denotes a leaving group.

  一种磷酸二酯衍生物，其通式表示为（1）：其中R1和R2中至少一个表示为离去基团。
• Nahlsgen optical resolution method
  申请人：KYOTO UNIVERSITY

  公开号：US10774098B2

  公开（公告）日：2020-09-15

  Provided is a method for separating the four optical isomers of Nahlsgen. The method according to the present invention for producing a mixture of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate includes subjecting a mixture of the four optical isomers, represented by Formula (1′), to fractional crystallization from water or from a solvent mixture of water and a water-soluble organic solvent, to precipitate a mixture of a compound represented by Formula (1-1′-1) and a compound represented by Formula (1-4′-1), where Formulae (1′), (1-1′-1), and (1-4′-1) are expressed as follows:

  本发明提供了一种分离 Nahlsgen 四种光学异构体的方法。根据本发明，生产 D-2-氨基-4-[(Rp)-(3-羧甲基苯氧基)(甲氧基)磷酰]丁酸水合物和 L-2-氨基-4-[(Sp)-(3-羧甲基苯氧基)(甲氧基)磷酰]丁酸水合物混合物的方法包括将式（1′）表示的四种光学异构体的混合物、从水中或从水和水溶性有机溶剂的混合溶剂中进行分馏结晶，析出由式(1-1′-1)表示的化合物和由式(1-4′-1)表示的化合物的混合物，其中式(1′)、(1-1′-1)和(1-4′-1)表示如下：
• Phosphonate-based irreversible inhibitors of human γ-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity
  作者：Akane Kamiyama、Mado Nakajima、Liyou Han、Kei Wada、Masaharu Mizutani、Yukiko Tabuchi、Akiko Kojima-Yuasa、Isao Matsui-Yuasa、Hideyuki Suzuki、Keiichi Fukuyama、Bunta Watanabe、Jun Hiratake

  DOI：10.1016/j.bmc.2016.08.050

  日期：2016.11

  gamma-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target. We report here the evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-([3-(carboxymethyl)phenoxy](methoyl)phosphoryl}butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivated the human enzyme significantly faster than the other phosphonates, and importantly did not inhibit a glutamine amidotransferase. The structure-activity relationships, X-ray crystallography with Escherichia coli GGT, sequence alignment and site-directed mutagenesis of human GGT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active-site residue Lys562 of human GGT for potent inhibition. GGsTop showed no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1 mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that could be used for various in vivo as well as in vitro biochemical studies. (C) 2016 Elsevier Ltd. All rights reserved.