benzyl (2RS,R_PS_P)-2-benzyloxycarbonylamino-4-{[4-(benzyloxycarbonyl)phenoxy](methoxy)phosphoryl}butanoate | 940963-69-9

• 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 (2RS,R_PS_P)-2-benzyloxycarbonylamino-4-{[4-(benzyloxycarbonyl)phenoxy](methoxy)phosphoryl}butanoate
• 英文别名: benzyl 2-(N-benzyloxycarbonylamino)-4-[4-(benzyloxycarbonyl)phenyl(methyl)phosphono]butanoate；benzyl 4-[methoxy-[4-oxo-4-phenylmethoxy-3-(phenylmethoxycarbonylamino)butyl]phosphoryl]oxybenzoate
• CAS: 940963-69-9
• 化学式: C₃₄H₃₄NO₉P
• 分子量: 631.619
• InChiKey: KMTWXNLGBMJGHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  45
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  benzyl (2RS,R_PS_P)-2-benzyloxycarbonylamino-4-{[4-(benzyloxycarbonyl)phenoxy](methoxy)phosphoryl}butanoate 在 5%-palladium/activated carbon 氢气 作用下， 以 水 、 溶剂黄146 为溶剂， 反应 2.2h， 以89%的产率得到(2RS,R_PS_P)-2-amino-4-[(4-carboxyphenoxy)(methoxy)phosphoryl]butanoic acid
  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
• 作为产物：
  描述：

  benzyl 2-benzyloxycarbonylamino-4-(dihydroxyphosphoryl)butanoate 在 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 生成 benzyl (2RS,R_PS_P)-2-benzyloxycarbonylamino-4-{[4-(benzyloxycarbonyl)phenoxy](methoxy)phosphoryl}butanoate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2016.08.050

文献信息

• 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。
• US8129557B2
  申请人：——

  公开号：US8129557B2

  公开（公告）日：2012-03-06
• 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.
• PHOSPHONIC ACID DIESTER DERIVATIVE AND METHOD FOR PRODUCING THEREOF
  申请人：Hiratake Jun

  公开号：US20090163725A1

  公开（公告）日：2009-06-25

  A phosphonic acid diester derivative represented by the following general formula (1): wherein at least one of R 1 and R 2 denotes a leaving group.

  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。