(1aS,3aS,7aR,7bS)-6,6-Dimethyl-hexahydro-1,5,7-trioxa-3-aza-cyclopropa[a]naphthalene-3-carboxylic acid tert-butyl ester | 792950-99-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (1aS,3aS,7aR,7bS)-6,6-Dimethyl-hexahydro-1,5,7-trioxa-3-aza-cyclopropa[a]naphthalene-3-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (1R,2S,4S,7S)-10,10-dimethyl-3,9,11-trioxa-6-azatricyclo[5.4.0.02,4]undecane-6-carboxylate
• CAS: 792950-99-3
• 化学式: C₁₄H₂₃NO₅
• 分子量: 285.34
• InChiKey: NGXXBVWFUFNSFP-MMWGEVLESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  60.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1aS,3aS,7aR,7bS)-6,6-Dimethyl-hexahydro-1,5,7-trioxa-3-aza-cyclopropa[a]naphthalene-3-carboxylic acid tert-butyl ester 在 硫酸 、 Amberlite IRA-410 (OH^- form) 、 Dowex 1-X₂ (OH^-) 作用下， 以 1,4-二氧六环 、 水 为溶剂， 以83%的产率得到1,5-dideoxy-1,5-imino-L-galactitol
  参考文献：
  名称：

  Biological Properties of d- and l-1-Deoxyazasugars

  摘要：

  L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyldonojirimycin (ido-DNJ) were prepared according to prior methods for the D-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although D-DNJ and D-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the nM range, L-DNJ and L-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the PM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. D-manno-DNJ is known as a much better inhibitor of alpha-L-fucosidase than a-mannosidase, while L-allo-DNJ was a better inhibitor than D-manno-DNJ of alpha-mannosidase. L-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-L-fucosidase with a K-i value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-L-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. D-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC50 = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while D-DNJ inhibiting alpha-glucosidase (IC50 = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although L-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC50 = 64 mu M), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.

  DOI：

  10.1021/jm0495881
• 作为产物：
  描述：

  tert-butyl (2S,3S)-3-hydroxy-2-(hydroxymethyl)-3,6-dihydro-2H-pyridine-1-carboxylate 在 sodium dihydrogenphosphate 、 4-甲基苯磺酸吡啶 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 生成 (1aS,3aS,7aR,7bS)-6,6-Dimethyl-hexahydro-1,5,7-trioxa-3-aza-cyclopropa[a]naphthalene-3-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Biological Properties of d- and l-1-Deoxyazasugars

  摘要：

  L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyldonojirimycin (ido-DNJ) were prepared according to prior methods for the D-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although D-DNJ and D-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the nM range, L-DNJ and L-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K-i values in the PM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. D-manno-DNJ is known as a much better inhibitor of alpha-L-fucosidase than a-mannosidase, while L-allo-DNJ was a better inhibitor than D-manno-DNJ of alpha-mannosidase. L-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-L-fucosidase with a K-i value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-L-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. D-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC50 = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while D-DNJ inhibiting alpha-glucosidase (IC50 = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although L-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC50 = 64 mu M), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.

  DOI：

  10.1021/jm0495881

文献信息

• Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors
  作者：Richard J. B. H. N. van den Berg、Tom Wennekes、Amar Ghisaidoobe、Wilma E. Donker-Koopman、Anneke Strijland、Rolf G. Boot、Gijsbert A. van der Marel、Johannes M. F. G. Aerts、Herman S. Overkleeft

  DOI：10.1021/ml200050s

  日期：2011.7.14

  N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with

  葡萄糖神经酰胺合酶 (GCS) 是一种已获批准的治疗戈谢病的药物靶点，被认为是对抗其他人类疾病（包括 2 型糖尿病）的有效靶点。临床药物N-丁基脱氧野尻霉素 (Zavesca) 被认为通过模拟其底物神经酰胺来抑制。在这项工作中，我们证明，与该模型中提出的相反，脱氧野尻霉素核心的 C2-羟基对于 GCS 抑制很重要。在这里，我们表明 C6-OH 似乎不那么重要，这可能为开发对其他糖加工酶（特别是作用于葡萄糖神经酰胺的水解酶）具有较低亲和力（与 Zavesca 相比）的 GCS 抑制剂制定指导方针。