(±)-1-azafagomine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (±)-1-azafagomine
• 英文别名: 1-azafagomine；(3S,4S,5S)-3-(hydroxymethyl)diazinane-4,5-diol
• 化学式: C₅H₁₂N₂O₃
• 分子量: 148.162
• InChiKey: PPPMSBCQTLJPKM-YUPRTTJUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  84.8
• 氢给体数：
  5
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (±)-1-azafagomine 在 sodium hydride 、 碳酸氢钠 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 、 paraffin oil 为溶剂， 反应 32.5h， 生成 N-Boc-tri-O-benzyl-1-azafagomine-N-butylcarboxamide
  参考文献：
  名称：

  α-，β-葡萄糖苷酶对1-N-羧酰胺-1-氮杂胺和5-表-1-氮杂胺的合成及评价

  摘要：

  从1-氮杂胺和5-表-1-氮杂胺获得1-N-羧酰胺1-氮杂胺和5-表-1-氮杂胺。在与不同的异氰酸酯反应形成脲之前，保护羟基和N-2哒嗪位置。除去保护基团，以18-23％的全球收率得到目标化合物。最终化合物针对α-和β-葡萄糖苷酶进行了测试。

  DOI：

  10.1016/j.carres.2014.06.015
• 作为产物：
  描述：

  (+/-)-2-hydroxymethyl-8-phenyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione 在 Oxone 、 高氯酸 、 1,1,1-三氟丙酮 、 碳酸氢钠 、 一水合肼 作用下， 以 乙腈 为溶剂， 反应 43.0h， 生成 (±)-1-azafagomine
  参考文献：
  名称：

  1-Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage

  摘要：

  Abstract(3,4‐trans‐4,5‐trans)‐4,5‐dihydroxy‐3‐hydroxymethylhexahydropyrida‐zine (16) was synthesized in four steps from 2,4‐pentadienol (22) and 4‐phenyl‐triazolin‐3,5‐dione (18) in an overall yield of 32%. In the first step a Diels‐Alder reaction between 18 and 22 gave (π)‐2‐hydroxymethyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]non‐3‐ene‐7,9‐dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3‐trans‐3,4‐trans)‐3,4‐dihydroxy‐2‐hydroxy‐methyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]‐nonane‐7,9‐dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of α‐and β‐glucosidase, isomaltase and glyco‐gen phosphorylase, while galactosidases and α‐mannosidase were not inhibited. The inhibition of β‐glucosidase is independent of pH, and was found to be due to unprotonated 16.

  DOI：

  10.1002/chem.19970030616

文献信息

• Enantiospecific Synthesis of 1-Azafagomine
  作者：Bettina V. Ernholt、Ib B. Thomsen、Anders Lohse、Igor W. Plesner、Kenneth B. Jensen、Rita G. Hazell、Xifu Liang、Astrid Jakobsen、Mikael Bols

  DOI：10.1002/(sici)1521-3765(20000117)6:2<278::aid-chem278>3.0.co;2-6

  日期：2000.1.17

  L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement

  糖苷酶抑制剂1-azafagomine的两种对映体形式首次从D-和L-木糖开始合成。将D-木糖转化为2,3,5-三苄基呋喃糖，将其与氨基甲酸叔丁酯还原胺化后，可以高收率得到被保护的1-肼基-1-脱氧戊糖醇。N-乙酰化，4-OH的甲磺酸化，Boc基团的去除，环化和脱保护得到（+）-1-azafagomine（（+）-1）。通过类似的反应序列，L-木糖被转化为（-）-1-氮杂花胺（（-）-1）。还研究了通过酶促途径和其他途径获得光学纯的1-氮杂谷氨酰胺。化合物（-）-1是有效的竞争性糖苷酶抑制剂，而（+）-1没有生物活性。由于抑制剂与酶的结合步骤缓慢，因此发现（-）-1对杏仁β-葡萄糖苷酶的抑制作用较慢，没有随后的构象重排。发现结合和释放的速率常数分别为3.3 x 10（4）M（-1）s（-1）和0.011 s（-1），产生Ki = 0.33 microM。
• Synthesis of (+)-Azafagomine from D-xylose
  作者：Bettina V. Ernholt、Ib B. Thomsen、Kenneth B. Jensen、Mikael Bols

  DOI：10.1055/s-1999-2716

  日期：1999.6

  L-glucose resembling enantiomer of the racemic glycosidase inhibitor azafagomine was synthesised from D-xylose and found to be inactive.

  用 D-木糖合成了类似外消旋糖苷酶抑制剂阿扎法戈明对映体的 L-木糖，结果发现该对映体没有活性。
• Synthetic studies of fluorinated analogues of 1-azafagomine: Remarkable nucleophilic substitution of fluorine by hydrazine
  作者：Ib Thomsen、Bettina V. Ernholt、Mikael Bols

  DOI：10.1016/s0040-4020(97)00588-7

  日期：1997.7

  (+/-)-5-fluoro-4-hydroxy-3-hydroxymethylhexahydropyridazine (7) and some other azafagomine analogues were synthesised with the aim of comparing their glycosidase inhibition to that of (+/-)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine (1-azafagomine). Both in the synthesis of 7 and in the attempted synthesis of 4,5-dihydroxy-3-fluoromethylhexahydropyridazine, a remarkable degree of nucleophilic substitution of fluorine by hydrazine was observed in the final deprotection step involving hydrazinolysis. Fluorine analogue 7 was a considerably weaker glycosidase inhibitor than I, suggesting that the 3-OH of 1 play a role in its binding by acting as a hydrogen bond donator. (C) 1997 Elsevier Science Ltd.

  (+/-)-5-氟-4-羟基-3-羟甲基六氢吡啶嗪(7)及其他一些aza-扇贝啶类似物的合成目的是比较它们对糖苷酶的抑制作用与(+/-)-4,5-二羟基-3-羟甲基六氢吡啶嗪(1-aza-扇贝啶)。在合成7以及尝试合成4,5-二羟基-3-氟甲基六氢吡啶嗪的过程中，在最终的去保护步骤中观察到了显著的氟被肼的亲核取代反应。氟类似物7的糖苷酶抑制作用比1弱得多，表明1中的3-OH在结合中起作用，作为氢键供体。 (C) 1997 Elsevier Science Ltd.
• The first combinatorial library of azasugar glycosidase inhibitors
  作者：Anders Lohse、Kenneth B. Jensen、Mikael Bols

  DOI：10.1016/s0040-4039(99)00317-2

  日期：1999.4

  A combinatorial library of 125 compounds with a structure consisting of 1-azafagomine linked at N-1 via an acetic acid linker to a variable tripeptide was synthesised. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Synthesis and deconvolution of the first combinatorial library of glycosidase inhibitors
  作者：Anders Lohse、Kenneth B Jensen、Karsten Lundgren、Mikael Bols

  DOI：10.1016/s0968-0896(99)00116-9

  日期：1999.9

  A combinatorial library of 125 compounds with a structure consisting of 1-azafagomine linked at N-1 via an acetic acid linker to a variable tripeptide was synthesised. The library was synthesised by Merrifield split and mix synthesis of the peptide, followed by capping with chloroacetate, regioselective nucleophilic substitution with 1-azafagomine and cleavage from the polymeric support. The library was screened for inhibition of beta-glucosidase, alpha-glucosidase and glycogen phosphorylase and found to display beta-glucosidase inhibition. Deconvolution of the library revealed that some inhibition was caused by all library members but the strongest inhibitor was clearly a compound having three hydroxyproline residues in the peptide fragment. This compound was a weaker but more selective inhibitor than 1-azafagomine itself.