2-(16-fluorohexadecyl)sulfanyl-4,5-dihydro-(1,2-dideoxy-α-D-glucopyranoso)[1,2-d]-1,3-oxazole

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(16-fluorohexadecyl)sulfanyl-4,5-dihydro-(1,2-dideoxy-α-D-glucopyranoso)[1,2-d]-1,3-oxazole
• 英文别名: (3aS,5R,6S,7S,7aR)-2-(16-fluorohexadecylsulfanyl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d][1,3]oxazole-6,7-diol
• 化学式: C₂₃H₄₂FNO₅S
• 分子量: 463.655
• InChiKey: CROBGKVKJCOLFO-BDHVOXNPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  31
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  16-溴-1-十六烷醇 在 二乙胺基三氟化硫 、 1,5,7-三氮杂双环[4.4.0]癸-5-烯 、 sodium methylate 、 碳酸氢钠 、 三乙胺 、 sodium iodide 作用下， 以 甲醇 、 二氯甲烷 、 丙酮 为溶剂， 反应 52.0h， 生成 2-(16-fluorohexadecyl)sulfanyl-4,5-dihydro-(1,2-dideoxy-α-D-glucopyranoso)[1,2-d]-1,3-oxazole
  参考文献：
  名称：

  Conformationally-locked N-glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease

  摘要：

  Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfany1-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian beta-glucosidase. Notably, their inhibitory potency against human beta-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of omega-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.002

文献信息

• Conformationally-locked N-glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease
  作者：Javier Castilla、Rocío Rísquez、Katsumi Higaki、Eiji Nanba、Kousaku Ohno、Yoshiyuki Suzuki、Yolanda Díaz、Carmen Ortiz Mellet、José M. García Fernández、Sergio Castillón

  DOI：10.1016/j.ejmech.2014.11.002

  日期：2015.1

  Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfany1-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian beta-glucosidase. Notably, their inhibitory potency against human beta-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of omega-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity. (C) 2014 Elsevier Masson SAS. All rights reserved.