(1S,4R)-6-iodo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one | 918452-17-2

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: (1S,4R)-6-iodo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one
• 英文别名: (1S,4R)-6-iodo-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[2.2.1]hept-5-en-3-one
• CAS: 918452-17-2
• 化学式: C₁₄H₁₄INO₂
• 分子量: 355.175
• InChiKey: UKPOWAZCYCEVGZ-GWCFXTLKSA-N

物化性质

• 沸点：
  484.9±45.0 °C(Predicted)
• 密度：
  1.71±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S,4R)-6-iodo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one 在 正丁基锂 、 N-氟代双苯磺酰胺 作用下， 生成 (+/-)-(3S,6R)-N-(4-methoxybenzyl)-1-azabicyclo[2.2.1]hept-4-en-2-one
  参考文献：
  名称：

  Fluorinated Conformationally Restricted γ-Aminobutyric Acid Aminotransferase Inhibitors

  摘要：

  On the basis of the structures of several potent inhibitor molecules for gamma-aminobutryric acid aminotransferase (GABA-AT) that were previously reported, six modified fluorine-containing conformationally restricted analogues were designed, synthesized, and tested as GABA-AT inhibitors. The syntheses of all six molecules followed from a readily synthesized ketone intermediate. Three of the molecules were found to be irreversible inhibitors of GABA-AT with comparable or larger k(inact)/K-I values than that of vigabatrin, a clinically used antiepilepsy drug, and the other three were reversible inhibitors. A possible mechanism for inactivation by one of the inactivators is proposed.

  DOI：

  10.1021/jm0608715
• 作为产物：
  描述：

  (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one 在 N-甲基吲哚酮 、 四丙基高钌酸铵 、 1,3-二溴-5,5-二甲基海因 、 偶氮二异丁腈 、 potassium tert-butylate 、 碘 、 三正丁基氢锡 、 potassium carbonate 、 一水合肼 、 三乙胺 作用下， 以 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 苯 为溶剂， 反应 80.5h， 生成 (1S,4R)-6-iodo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one
  参考文献：
  名称：

  Fluorinated Conformationally Restricted γ-Aminobutyric Acid Aminotransferase Inhibitors

  摘要：

  On the basis of the structures of several potent inhibitor molecules for gamma-aminobutryric acid aminotransferase (GABA-AT) that were previously reported, six modified fluorine-containing conformationally restricted analogues were designed, synthesized, and tested as GABA-AT inhibitors. The syntheses of all six molecules followed from a readily synthesized ketone intermediate. Three of the molecules were found to be irreversible inhibitors of GABA-AT with comparable or larger k(inact)/K-I values than that of vigabatrin, a clinically used antiepilepsy drug, and the other three were reversible inhibitors. A possible mechanism for inactivation by one of the inactivators is proposed.

  DOI：

  10.1021/jm0608715

文献信息

• Rational Design, Synthesis, and Mechanism of (3<i>S</i>,4<i>R</i>)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase
  作者：Wei Zhu、Arseniy Butrin、Rafael D. Melani、Peter F. Doubleday、Glaucio Monteiro Ferreira、Mauricio T. Tavares、Thahani S. Habeeb Mohammad、Brett A. Beaupre、Neil L. Kelleher、Graham R. Moran、Dali Liu、Richard B. Silverman

  DOI：10.1021/jacs.2c00924

  日期：2022.3.30

  Human ornithine aminotransferase (hOAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT

  人鸟氨酸转氨酶 (hOAT) 是一种 5'-磷酸吡哆醛 (PLP) 依赖性酶，其活性位点与 γ-氨基丁酸转氨酶 (GABA-AT) 相似。最近，hOAT 的药理学抑制被认为是肝细胞癌的潜在治疗方法。在这项工作中，我们首先研究了两种著名的 GABA-AT 灭活剂（CPP-115和OV329）对 hOAT 的灭活机制。受这两种氨基转移酶灭活机制差异的启发，设计并合成了一系列类似物，从而发现了类似物10b作为一种高选择性和有效的 hOAT 抑制剂。完整的蛋白质质谱、蛋白质晶体学和透析实验表明，10b在 hOAT 的活性位点转化为不可逆的紧密结合加合物 ( 34 )，不饱和类似物 ( 11 )也是如此。10b和11之间的动力学研究比较表明，活性中间体 ( 17b ) 仅在 hOAT 中产生，而不在 GABA-AT 中产生。分子对接研究和 p Ka计算计算突出了手性和环内双键对抑制活性的重要性。10
• [EN] (3S,4R)-3-AMINO-4-(DIFLUOROMETHYL)CYCLOPENT-1-ENE-1-CARBOXYLIC ACID AND RELATED COMPOUNDS AS SELECTIVE INACTIVATORS OF ORNITHINE AMINOTRANSFERASE<br/>[FR] ACIDE (3S,4R)-3-AMINO-4-(DIFLUOROMÉTHYL) CYCLOPENT-1-ÈNE-1-CARBOXYLIQUE ET COMPOSÉS APPARENTÉS UTILISÉS EN TANT QU'ACTIVATEURS SÉLECTIFS DE L'ORNITHINE AMINOTRANSFÉRASE
  申请人：[en]NORTHWESTERN UNIVERSITY

  公开号：WO2023164715A2

  公开（公告）日：2023-08-31

  Disclosed are amino, halo-substituted cyclopentene, cyclopentane, or 4- methylenecyclopent- l-ene carboxylic acid compounds. The disclosed compounds and compositions thereof may be utilized in methods for modulating human ornithine δ- aminotransferase(hOAT) activity, including methods for treating diseases or disorders associated withhOAT activity or expression such as cell proliferative diseases and disorders.