5'-deoxy-2',3'-O-isopropylidene-5'-[(2-phthalimidooxyethyl)methylamino]adenosine | 121032-12-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 5'-deoxy-2',3'-O-isopropylidene-5'-[(2-phthalimidooxyethyl)methylamino]adenosine
• 英文别名: 2-[2-[[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl-methylamino]ethoxy]isoindole-1,3-dione
• CAS: 121032-12-0
• 化学式: C₂₄H₂₇N₇O₆
• 分子量: 509.522
• InChiKey: QQSJDSIYBHTWFE-CXIOKZBNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  147
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  5'-deoxy-2',3'-O-isopropylidene-5'-[(2-phthalimidooxyethyl)methylamino]adenosine 在 硫酸 作用下， 以 水 为溶剂， 反应 3.0h， 以100 mg的产率得到5'-[(2-aminooxyethyl)methylamino]-5'-deoxyadenosine sulfate
  参考文献：
  名称：

  New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C⁸ Substitution in Structural Analogues of S-Adenosylmethionine

  摘要：

  S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C(8)-substituted adenine analogues bound in the active site.

  DOI：

  10.1021/jm801126a
• 作为产物：
  描述：

  N-羟基邻苯二甲酰亚胺 、 5'-deoxy-2',3'-O-isopropylidene-5'-[(2-hydroxyethyl)methylamino]adenosine 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 0.13h， 以61%的产率得到5'-deoxy-2',3'-O-isopropylidene-5'-[(2-phthalimidooxyethyl)methylamino]adenosine
  参考文献：
  名称：

  [EN] 5'-SUBSTITUTED ADENOSYNES, PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE
  [FR] ADÉNOSYNES SUBSTITUÉES EN 5', PRÉPARATION DE CELLES-CI ET UTILISATION COMME INHIBITEUR DE LA S-ADÉNOSYLMÉTHIONINE DÉCARBOXYLASE

  摘要：

  公开号：

  WO2009018541A8

文献信息

• 5',-SUBSTITUTED ADENOSYNES PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE
  申请人：Secrist, III John A.

  公开号：US20110009354A1

  公开（公告）日：2011-01-13

  The crystal structure of the complex of S-adenosylmethionine methyl ester with hΛdoMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5′-deoxy-5′-[N-methyl-N-[2-(aminooxy)ethyl]amino-8-methyl]adenosine (MAOEMA) and 5′-deoxy-5′-[N-methyl-N-[4-(aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.

  S-腺苷甲硫氨酸甲酯与hΛdoMetDC F223A复合物的晶体结构已被确定，该突变体中F7、腺嘌呤和F223的芳香环堆叠被消除。该突变体与酯的结构表明，配体仍通过与F7的π-π相互作用、与Glu67骨架的氢键和静电相互作用来维持同构构象。合成了几个AdoMet底物类似物系列，这些类似物在腺嘌呤的8位具有不同的取代基，分析它们抑制hAdoMetDC的能力。为了理解这些结果，通过虚拟建模酶抑制剂复合物和人类AdoMetDC与5'-去氧-5'-[N-甲基-N-[2-(氨氧)乙基]氨基-8-甲基]腺苷(MAOEMA)和5'-去氧-5'-[N-甲基-N-[4-(氨氧)丁基]氨基-8-乙基]腺苷(MAOBEA)在活性位点的晶体结构已被实验确定。
• 5'-substituted adenosynes, preparation thereof and use as inhibitors of s-adenosylmethionine decarboxylase.
  申请人：Southern Research Institute

  公开号：EP2574616A2

  公开（公告）日：2013-04-03

  The crystal structure of the complex of S-adenosylmethionine methyl ester with hAdoMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5'-deoxy-5'-[N-methyl-N-[2-(aminooxy)ethyl]ainino-8-methyl]adenosine (MAOEMA) and 5'-deoxy-5'-[N-methyl-N-[4-(aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.

  S- 腺苷蛋氨酸甲酯与 hAdoMetDC F223A 复合物的晶体结构，F223A 是一种突变体，在这种突变体中，F7、腺嘌呤和 F223 的芳香环堆积将被消除。这种带有酯的突变体的结构显示，配体仍然通过与 F7 的 pi-pi 相互作用、与 Glu67 骨架的氢键以及静电作用保持合成构象。我们合成了几个系列的 AdoMet 底物类似物，它们在腺嘌呤的 8 位上有多种取代基，并分析了它们抑制 hAdoMetDC 的能力。为了理解这些结果，实验测定了酶抑制剂复合物的虚拟模型以及人 AdoMetDC 与 5'-脱氧-5'-[N-甲基-N-[2-（氨基氧）乙基]氨基-8-甲基]腺苷（MAOEMA）和 5'-脱氧-5'-[N-甲基-N-[4-（氨基氧）丁基]氨基-8-乙基]腺苷（MAOBEA）在活性位点的晶体结构。
• [EN] 5'-SUBSTITUTED ADENOSYNES, PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE<br/>[FR] ADÉNOSYNES SUBSTITUÉES EN 5', PRÉPARATION DE CELLES-CI ET UTILISATION COMME INHIBITEUR DE LA S-ADÉNOSYLMÉTHIONINE DÉCARBOXYLASE
  申请人：SOUTHERN RES INST

  公开号：WO2009018541A8

  公开（公告）日：2010-03-04
• 5'-SUBSTITUTED ADENOSYNES, PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE
  申请人：Southern Research Institute

  公开号：EP2170057A1

  公开（公告）日：2010-04-07
• US8637485B2
  申请人：——

  公开号：US8637485B2

  公开（公告）日：2014-01-28