(2S,4R)-1-acetyl-4-hydroxy-N-methylpyrrolidine-2-carboxamide | 19746-36-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,4R)-1-acetyl-4-hydroxy-N-methylpyrrolidine-2-carboxamide
• 英文别名: N-acetyl-trans-4-hydroxy-L-proline-N'-methylamide；Ac-Hyp-NMe；trans-1-acetyl-4-hydroxy-L-proline-methylamide；trans-1-Acetyl-4-hydroxy-L-prolin-methylamid；(4r)-1-Acetyl-4-Hydroxy-N-Methyl-L-Prolinamide
• CAS: 19746-36-2
• 化学式: C₈H₁₄N₂O₃
• 分子量: 186.211
• InChiKey: XAZYBLFYZNUKHD-RQJHMYQMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (2S,4R)-1-(t-butoxycarbonyl)-2-methylcarbamoyl-4-hydroxypyrrolidine 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 (2S,4R)-1-acetyl-4-hydroxy-N-methylpyrrolidine-2-carboxamide
  参考文献：
  名称：

  Alkyl 3-Position Substituents Retard the Isomerization of Prolyl and Hydroxyprolyl Amides in Water

  摘要：

  The influence of alkyl 3-position substituents on the rate of amide isomerization N-terminal to proline and hydroxyproline has been explored via the synthesis and analysis of (2S)-N-(acetyl)proline N'-methylamide (1), (2S,4R)- and (2S,4S)-N-acetyl-4-hydroxyproline N'-methylamides 2 and 3, and their respective 3,3-dimethyl analogues 4-6. The relative populations of the amide cis and trans isomers as well as the rates for cis-to-trans and trans-to-cis isomerization of 1-6 in water were ascertained by NMR spectroscopy and magnetization transfer experiments. The relative populations of free C-terminal and hydrogen-bonded amides in the gamma-turn conformation were also estimated by integrating the N-H stretch absorbances in the FT-IR spectra of 1 and 4 in CHCl3. In addition, the structure of the amide trans isomer of (2S,4S)-N-acetyl-3,3-dimethyl-4-hydroxyproline N'-methylamide (6) was determined in the solid state by X-ray crystallographic analysis. In prolyl peptides 1-6, the 3,3-dimethyl and hydroxyl substituents had little effect on the amide isomer equilibrium. A dramatic decrease in the rate of cis-to-trans amide isomerization was observed for N-acetyl-3,3-dimethylproline N'-methylamide (4), which exhibited a k(ct) nearly 7-fold slower than that of 1. Similar effects of the 3,3-dimethyl substituents were observed, albeit to a lesser degree, in the cases of the hydroxyprolyl peptides. The FT-IR data for 4 and X-ray data for 6 both demonstrated that the 3,3-dimethyl substituents restricted the proline psi dihedral angle and prevented the formation of a gamma-turn conformation, having a seven-membered hydrogen bond between the C-terminal amide NH and N-terminal amide carbonyl. Furthermore, restriction of the psi dihedral angle by the methyl groups was observed in systematic computational conformational analyses of 1-6, in which the psi and omega dihedral angles were rotated at 30 degrees intervals and the energies of the local minima were determined. Retardation of the rate of cis-to-trans amide isomerization in the dimethyl analogues may be attributed to steric interactions favoring a psi dihedral angle at which the C-terminal amide carbonyl destabilizes the transition state through Coulomb repulsion of either the developing nitrogen lone pair or the carbonyl oxygen of the pyramidalized N-terminal amide. The consequences of S-alkyl and 4-hydroxyl substituents on the rate of proline amide isomerization in water, which was observed to decrease in the order 1 approximate to 3 > 2 > 6 > 5 > 4, may result from influences on the psi, dihedral angle geometry, inductive effects, and intramolecular hydrogen bonding.

  DOI：

  10.1021/jo980673o

文献信息

• Substituted Isoquinolinones and Quinazolinones
  申请人：BERGHAUSEN Joerg

  公开号：US20110230457A1

  公开（公告）日：2011-09-22

  The invention relates to substituted nitrogen containing bicyclic heterocycles of the formula (I) wherein Z is CH 2 or N—R 4 and X, R 1 , R 2 , R 4 , R 6 , R 7 and n are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

  这项发明涉及公式（I）中的取代氮含有的双环杂环化合物，其中Z为CH2或N—R4，X、R1、R2、R4、R6、R7和n的定义如描述中所述。这类化合物适用于治疗由MDM2和/或MDM4的活性介导的疾病或疾病变体。
• Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  申请人：YALE UNIVERSITY

  公开号：US20140356322A1

  公开（公告）日：2014-12-04

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是作为本发明的双功能化合物对各种被降解和/或受到抑制的多肽和其他蛋白质的抑制剂。具体而言，本发明涉及含有一端结合泛素连接酶的VHL配体，另一端结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。本发明展示了与本发明化合物相关的广泛的药理活性范围，与靶向多肽的降解/抑制一致。
• Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction
  作者：Dennis L. Buckley、Inge Van Molle、Peter C. Gareiss、Hyun Seop Tae、Julien Michel、Devin J. Noblin、William L. Jorgensen、Alessio Ciulli、Craig M. Crews

  DOI：10.1021/ja209924v

  日期：2012.3.14

  E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extraordinarily challenging as modulation of E3 ligase activities requires the targeting of protein–protein interactions. Using rational design, we have

  E3 泛素连接酶结合蛋白质靶标，导致其泛素化和随后的降解，由于其出色的底物特异性，是有吸引力的药物靶标。然而，小分子抑制剂的开发已证明极具挑战性，因为调节 E3 连接酶活性需要靶向蛋白质-蛋白质相互作用。通过合理的设计，我们生成了第一个靶向 von Hippel-Lindau 蛋白 (VHL) 的小分子，VHL 是 E3 连接酶的底物识别亚基，也是癌症、慢性贫血和缺血的重要靶点。我们还获得了与我们最有效的抑制剂结合的 VHL 的晶体结构，证实该化合物模拟了转录因子 HIF-1α（VHL 的底物）的结合模式。
• Effects of Glycosylation of (2<i>S</i>,4<i>R</i>)-4-Hydroxyproline on the Conformation, Kinetics, and Thermodynamics of Prolyl Amide Isomerization
  作者：Neil W. Owens、Craig Braun、Joe D. O'Neil、Kirk Marat、Frank Schweizer

  DOI：10.1021/ja073488d

  日期：2007.9.1

  the peptide backbone. As a consequence, there is a reduction in the energy difference between the prolyl amide cis and trans isomers, making them nearly isoenergetic; this leads to higher cis N-terminal amide content relative to the other amino acids. Moreover, the isomerization of the prolyl amide bond has been shown to be the ratedetermining step in the folding pathways of many peptides and proteins

  Hyp-糖基化对肽骨架构象的构象影响。Hyp 和脯氨酸 (Pro) 在蛋白氨基酸中是独一无二的，因为它们的特点是 o 二面角的有限旋转（图 1），因为它们的侧链与肽主链融合。因此，脯氨酰胺顺式和反式异构体之间的能量差减小，使它们几乎等能；这导致相对于其他氨基酸更高的顺式 N 端酰胺含量。此外，脯氨酰胺键的异构化已被证明是许多肽和蛋白质折叠途径中的速率决定步骤。4 在本文中，我们描述了 Hyp 的半乳糖基化对脯氨酰 N 端酰胺异构化的构象以及热力学和动力学的影响。
• SUBSTITUTED ISOQUINOLINONES AND QUINAZOLINONES
  申请人：Novartis AG

  公开号：US20130281473A1

  公开（公告）日：2013-10-24

  The invention relates to substituted nitrogen containing bicyclic heterocycles of the formula (I) wherein Z is CH 2 or N—R 4 and X, R 1 , R 2 , R 4 , R 6 , R 7 and n are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

  本发明涉及式(I)的取代氮含杂环的双环杂环化合物，其中Z是CH2或N-R4，X，R1，R2，R4，R6，R7和n的定义如说明书中所定义。这类化合物适用于治疗由MDM2和/或MDM4的活性或其变异体介导的疾病或疾病。