(5R,7R,8S,9S,10R)-7-(hydroxymethyl)-3-(4-toluyl)-1,6-dioxa-2-azaspiro[4,5]dec-2-ene-8,9,10-triol | 1197825-76-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5R,7R,8S,9S,10R)-7-(hydroxymethyl)-3-(4-toluyl)-1,6-dioxa-2-azaspiro[4,5]dec-2-ene-8,9,10-triol
• 英文别名: Glucopyranosylidene-spiro-isoxazoline, 4b；(5R,6R,7S,8S,9R)-9-(hydroxymethyl)-3-(4-methylphenyl)-1,10-dioxa-2-azaspiro[4.5]dec-2-ene-6,7,8-triol
• CAS: 1197825-76-5
• 化学式: C₁₅H₁₉NO₆
• 分子量: 309.319
• InChiKey: GTYOYEGMJMKJRE-UXXRCYHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  p-methylbenzaldehyde oxime 在 N-氯代丁二酰亚胺 、 sodium methylate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (5R,7R,8S,9S,10R)-7-(hydroxymethyl)-3-(4-toluyl)-1,6-dioxa-2-azaspiro[4,5]dec-2-ene-8,9,10-triol
  参考文献：
  名称：

  Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition

  摘要：

  Glycogen phosphorylase (GP) is a target for the treatment of hyperglycaemia in the context of type 2 diabetes. This enzyme is responsible for the depolymerization of glycogen into glucose thereby affecting the levels of glucose in the blood stream. Twelve new D-glucopyranosylidene-spiro-isoxazolines have been prepared from O-peracylated exo-D-glucals by regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides generated in situ by treatment of the corresponding oximes with bleach. This mild and direct procedure appeared to be applicable to a broad range of substrates. The corresponding 0-unprotected spiro-isoxazolines were evaluated as glycogen phosphorylase (GP) inhibitors and exhibited IC50 values ranging from 1 to 800 mu M. Selected inhibitors were further evaluated in vitro using rat and human hepatocytes and exhibited significant inhibitory properties in the primary cell culture. Interestingly, when tested with human hepatocytes, the tetra-O-acetylated spiro-isoxazoline bearing a 2-naphthyl residue showed a much lower IC50 value (2.5 mu M), compared to that of the 0-unprotected analog (19.95 mu M). The most promising compounds were investigated in Zucker fa/fa rat model in acute and sub-chronic assays and decreased hepatic glucose production, which is known to be elevated in type 2 diabetes. This indicates that glucose-based spiro-isoxazolines can be considered as anti-hyperglycemic agents in the context of type 2 diabetes. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.12.004

文献信息

• Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors
  作者：Mahmoud Benltifa、Joseph M. Hayes、Sébastien Vidal、David Gueyrard、Peter G. Goekjian、Jean-Pierre Praly、Gregory Kizilis、Costas Tiraidis、Kyra-Melinda Alexacou、Evangelia D. Chrysina、Spyros E. Zographos、Demetres D. Leonidas、Georgios Archontis、Nikos G. Oikonomakos

  DOI：10.1016/j.bmc.2009.08.060

  日期：2009.10

  A series of glucopyranosylidene-spiro-isoxazolines was prepared through regio- and stereoselective [3+2]-cycloaddition between the methylene acetylated exo-glucal and aromatic nitrile oxides. The deprotected cycloadducts were evaluated as inhibitors of muscle glycogen phosphorylase b. The carbohydrate-based family of five inhibitors displays K(i) values ranging from 0.63 to 92.5 microM. The X-ray structures of the enzyme-ligand complexes show that the inhibitors bind preferentially at the catalytic site of the enzyme retaining the less active T-state conformation. Docking calculations with GLIDE in extra-precision (XP) mode yielded excellent agreement with experiment, as judged by comparison of the predicted binding modes of the five ligands with the crystallographic conformations and the good correlation between the docking scores and the experimental free binding energies. Use of docking constraints on the well-defined positions of the glucopyranose moiety in the catalytic site and redocking of GLIDE-XP poses using electrostatic potential fit-determined ligand partial charges in quantum polarized ligand docking (QPLD) produced the best results in this regard.
• Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition
  作者：David Goyard、Bálint Kónya、Aikaterini S. Chajistamatiou、Evangelia D. Chrysina、Jérémy Leroy、Sophie Balzarin、Michel Tournier、Didier Tousch、Pierre Petit、Cédric Duret、Patrick Maurel、László Somsák、Tibor Docsa、Pál Gergely、Jean-Pierre Praly、Jacqueline Azay-Milhau、Sébastien Vidal

  DOI：10.1016/j.ejmech.2015.12.004

  日期：2016.1

  Glycogen phosphorylase (GP) is a target for the treatment of hyperglycaemia in the context of type 2 diabetes. This enzyme is responsible for the depolymerization of glycogen into glucose thereby affecting the levels of glucose in the blood stream. Twelve new D-glucopyranosylidene-spiro-isoxazolines have been prepared from O-peracylated exo-D-glucals by regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides generated in situ by treatment of the corresponding oximes with bleach. This mild and direct procedure appeared to be applicable to a broad range of substrates. The corresponding 0-unprotected spiro-isoxazolines were evaluated as glycogen phosphorylase (GP) inhibitors and exhibited IC50 values ranging from 1 to 800 mu M. Selected inhibitors were further evaluated in vitro using rat and human hepatocytes and exhibited significant inhibitory properties in the primary cell culture. Interestingly, when tested with human hepatocytes, the tetra-O-acetylated spiro-isoxazoline bearing a 2-naphthyl residue showed a much lower IC50 value (2.5 mu M), compared to that of the 0-unprotected analog (19.95 mu M). The most promising compounds were investigated in Zucker fa/fa rat model in acute and sub-chronic assays and decreased hepatic glucose production, which is known to be elevated in type 2 diabetes. This indicates that glucose-based spiro-isoxazolines can be considered as anti-hyperglycemic agents in the context of type 2 diabetes. (C) 2015 Elsevier Masson SAS. All rights reserved.