(3R,4R,5S)-5-(羟基甲基)-3,4-哌啶二醇 | 202979-51-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: (3R,4R,5S)-5-(羟基甲基)-3,4-哌啶二醇
• 英文名称: 5-epi-isofagomine
• 英文别名: (3R,4R,5S)-5-(hydroxymethyl)piperidine-3,4-diol
• CAS: 202979-51-9
• 化学式: C₆H₁₃NO₃
• 分子量: 147.174
• InChiKey: QPYJXFZUIJOGNX-KVQBGUIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 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：
  72.7
• 氢给体数：
  4
• 氢受体数：
  4

制备方法与用途

用途
这是一种选择性强、活性极高的β-葡萄糖苷酶抑制剂（Ki值为0.11μM）。

反应信息

• 作为反应物：
  描述：

  2-(10-chloroanthracen-9-yl)acetaldehyde 、 (3R,4R,5S)-5-(羟基甲基)-3,4-哌啶二醇 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 、 氯仿 为溶剂， 以26%的产率得到N-(2-(10-chloroanthracen-9-yl)ethyl)iso-L-gulo-isofagomine
  参考文献：
  名称：

  合成新型荧光pH指示剂/糖苷酶抑制剂异黄酮衍生物

  摘要：

  为了检查酶活性位点的pH条件，需要质子化时具有开/关荧光的抑制剂。在此，将有效的糖苷酶抑制剂异黄酮转化为“糖苷酶荧光指示剂”。

  DOI：

  10.1002/ejoc.202000522
• 作为产物：
  描述：

  槟榔碱 在 氢氧化钾 、 锂硼氢 、 1-氯乙基氯甲酸酯 、 三乙基硼氢化锂 、 三乙胺 、 间氯过氧苯甲酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 甲苯 为溶剂， 反应 11.58h， 生成 (3R,4R,5S)-5-(羟基甲基)-3,4-哌啶二醇
  参考文献：
  名称：

  Iminosugars: potential inhibitors of liver glycogen phosphorylase

  摘要：

  The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S); (3R,4R,5S) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is reported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomers as well as of a series of N-substituted derivatives of the (3R,4R,SR)-isomer and selected hydroxypiperidine analogues on liver glycogen phosphorylase (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also showed that all three hydroxy groups should be present and could not be substituted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivatives of Isofagagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 muM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituents. Furthermore, we found that it was not enough to assure inhibitory effect to have the (R,,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol analogue, showed an IC50 value of 200 muM compared to 0.7 muM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 muM. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00291-1

文献信息

• 1-<i>N</i>-Iminosugars:  Potent and Selective Inhibitors of β-Glycosidases
  作者：Yoshitaka Ichikawa、Yasuhiro Igarashi、Mie Ichikawa、Yoshitomo Suhara

  DOI：10.1021/ja973443k

  日期：1998.4.1

  are both highly potent and selective for β-glycosidases. Designed on the basis of the transition-state model of the β-glucosidase reaction, these iminosugar inhibitors differ from the currently available inhibitors in possessing a nitrogen atom at the anomeric position of the pyranose ring, thereby generating a positive charge on the anomeric position rather than on the ring oxygen of the sugar. Their

  合成了一系列 1-N-亚氨基糖，以满足对高效且对 β-糖苷酶具有选择性的糖苷酶抑制剂的需求。基于β-葡萄糖苷酶反应的过渡态模型设计，这些亚氨基糖抑制剂与目前可用的抑制剂的不同之处在于在吡喃糖环的异头位置拥有一个氮原子，从而在异头位置产生正电荷而不是比在糖的环氧上。他们的合成，从容易获得的碳水化合物衍生物开始，包括 (i) 引入氨基官能团作为叠氮基，(ii) 形成具有还原胺化作用的 1-N-亚氨基吡喃糖环，以及 (iii) 立体选择性引入羟甲基或甲基，并以高度立体选择性和有效的方式完成。
• Synthesis of 5-epi-Isofagomine via Asymmetric Chelate–Enolate Claisen Rearrangement
  作者：Christiane Schneider、Uli Kazmaier

  DOI：10.1002/(sici)1099-0690(199806)1998:6<1155::aid-ejoc1155>3.0.co;2-g

  日期：1998.6

  Polyhydroxylated piperidines are an interesting class of glycosidase inhibitors. Chelate enolate Claisen rearrangement of N-protected chiral amino acid esters gives rise to γ,δ-unsaturated amino acids, which can be converted to this type of alkaloids. The potential glycosidase inhibitor 5-epi-isofagomine (5) was synthesized by this approach in a highly stereoselective fashion.

  多羟基哌啶是一类有趣的糖苷酶抑制剂。N-保护的手性氨基酸酯的螯合烯醇克莱森重排产生γ,δ-不饱和氨基酸，其可以转化为这种类型的生物碱。潜在的糖苷酶抑制剂 5-epi-isofagomine (5) 是通过这种方法以高度立体选择性的方式合成的。
• Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars
  作者：Y. Suman Reddy、Pavan K. Kancharla、Rashmi Roy、Yashwant D. Vankar

  DOI：10.1039/c2ob06851f

  日期：——

  Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.

  通过实施2- C-羟甲基糖的氮杂-克莱森重排作为关键步骤，已经实现了异黄酮的合成。上述重排也已用于合成生物学上重要的多羟基哌啶骨架，例如异半乳糖胺，对-异半乳糖胺及其类似物和一些其他的作为糖苷酶抑制剂的氮杂糖。
• Application of the asymmetric chelate-enolate claise rearrangement to the synthesis of 5-epi-isofagomine
  作者：Uli Kazmaier、Christiane Schneider

  DOI：10.1016/s0040-4039(97)10855-3

  日期：1998.2

  Chelate-enolate Claisen rearrangement of a N-protected chiral amino acid ester gave rise to a gamma,delta-unsaturated amino acid, which could be converted to the potential glycosidase inhibitor 5-epi-isofagomine (9) in a straightforward and a highly stereoselective fashion. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Docking and SAR studies of d- and l-isofagomine isomers as human β-glucocerebrosidase inhibitors
  作者：Atsushi Kato、Saori Miyauchi、Noriko Kato、Robert J. Nash、Yuichi Yoshimura、Izumi Nakagome、Shuichi Hirono、Hiroki Takahata、Isao Adachi

  DOI：10.1016/j.bmc.2011.04.011

  日期：2011.6

  We report the structure-activity relationship of a series of D-, and L-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of D-isofagomines enhanced the potency toward beta-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, D-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. L-Isofagomine was also a fairly potent inhibitor of human beta-glucocerebrosidase, with an IC50 value of 8.7 mu M. A molecular docking study revealed that the positions and orientations of the piperidine ring of D-3-epi-isofagomine in the binding site was similar to that of D-isofagomine, while D-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that D-3,4-di-epi-isofagomine can not bind to beta-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease. (C) 2011 Elsevier Ltd. All rights reserved.