2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester | 1370018-07-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester
• 英文别名: 1-(tert-butoxycarbonyl)-2-oxopyrrolidine-3-carboxylic acid；1-[(tert-Butoxy)carbonyl]-2-oxopyrrolidine-3-carboxylic acid；1-[(2-methylpropan-2-yl)oxycarbonyl]-2-oxopyrrolidine-3-carboxylic acid
• CAS: 1370018-07-7
• 化学式: C₁₀H₁₅NO₅
• 分子量: 229.233
• InChiKey: NOXJAVAPSWUNTK-UHFFFAOYSA-N

物化性质

• 沸点：
  425.8±38.0 °C(Predicted)
• 密度：
  1.304±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P264,P270,P271,P280,P301+P312,P302+P352,P304+P340,P330,P363,P501
• 危险性描述：
  H302,H312,H332

反应信息

• 作为反应物：
  描述：

  2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 在 1-丙基磷酸酐 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 3.0h， 生成 N-[(3-chloro-5-fluoro-phenyl)methyl]-2-oxo-pyrrolidine-3-carboxamide
  参考文献：
  名称：

  Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors

  摘要：

  Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign I la was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 mu M. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.

  DOI：

  10.1021/acs.jmedchem.9b00041
• 作为产物：
  描述：

  1-(叔丁氧羰基)-2-吡咯烷酮 在 palladium 10% on activated carbon 、 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 为溶剂， -78.0~20.0 ℃ 、200.0 kPa 条件下， 反应 4.0h， 生成 2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester
  参考文献：
  名称：

  Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors

  摘要：

  Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign I la was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 mu M. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.

  DOI：

  10.1021/acs.jmedchem.9b00041

文献信息

• Copper-catalysed approach to spirocyclic oxindoles via a direct C–H, Ar-H functionalisation
  作者：Catherine L. Moody、Vilius Franckevičius、Pauline Drouhin、Johannes E.M.N. Klein、Richard J.K. Taylor

  DOI：10.1016/j.tetlet.2012.01.120

  日期：2012.4

  A practical and efficient entry to spirocyclic oxindoles from readily accessible anilide precursors, using only catalytic amounts of an inexpensive copper salt together with air as the sole re-oxidant, is described. In addition to providing access to a broad range of spiro-oxindole products, the utility of this method is demonstrated in a formal synthesis of the natural product, horsfiline. (C) 2012 Elsevier Ltd. All rights reserved.
• Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors
  作者：Timo Heinrich、Jeyaprakashnarayanan Seenisamy、Beatrix Blume、Jörg Bomke、Michel Calderini、Uwe Eckert、Manja Friese-Hamim、Rainer Kohl、Martin Lehmann、Birgitta Leuthner、Djordje Musil、Felix Rohdich、Frank T. Zenke

  DOI：10.1021/acs.jmedchem.9b00041

  日期：2019.5.23

  Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign I la was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 mu M. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.