methyl N⁵,N⁵-dimethyl-L-glutaminate | 142165-93-3

• 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: methyl N⁵,N⁵-dimethyl-L-glutaminate
• 英文别名: (S)-Methyl 2-amino-5-(dimethylamino)-5-oxopentanoate；methyl (2S)-2-amino-5-(dimethylamino)-5-oxopentanoate
• CAS: 142165-93-3
• 化学式: C₈H₁₆N₂O₃
• 分子量: 188.227
• InChiKey: ISUXQMGYPFMDAZ-LURJTMIESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  13
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl N⁵,N⁵-dimethyl-L-glutaminate 在 lithium hydroxide monohydrate 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 13.0h， 生成
  参考文献：
  名称：

  Enzyme Inhibition by Hydroamination: Design and Mechanism of a Hybrid Carmaphycin-Syringolin Enone Proteasome Inhibitor

  摘要：

  Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and alpha,beta-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.

  DOI：

  10.1016/j.chembiol.2014.04.010
• 作为产物：
  描述：

  N-叔丁氧羰基-L-谷氨酸 1-甲酯 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 methyl N⁵,N⁵-dimethyl-L-glutaminate
  参考文献：
  名称：

  Antirheumatic Agents. III. Novel Methotrexate Derivatives Bearing an Indoline Ring and a Modified Ornithine or Glutamic Acid.

  摘要：

  描述了多种具有吲哚环的甲氨蝶呤（MTX）衍生物的合成、生物学特征及其结构-活性关系。特别是，与MTX相比，Nδ-(3-羧基苯基)-Nα-[1-[(2, 4-二氨基居普噻啶-6-基)-甲基]吲哚-5-基氨基]-L-谷氨酸（3d）在从健康志愿者获得的人外周血单核细胞上表现出增强的抗增殖效果。

  DOI：

  10.1248/cpb.45.1146

文献信息

• [EN] PEPTIDOMIMETIC N5-METHYL-N2-(NONANOYL-L-LEUCYL)-L-GLUTAMINATE DERIVATIVES, TRIAZASPIRO[4.14]NONADECANE DERIVATIVES AND SIMILAR COMPOUNDS AS INHIBITORS OF NOROVIRUS AND CORONAVIRUS REPLICATION<br/>[FR] DÉRIVÉS DE N5-MÉTHYL-N2-(NONANOYL-L-LEUCYL)-L-GLUTAMINATE PEPTIDOMIMÉTIQUES, DÉRIVÉS DE TRIAZASPIRO[4.14]NONADÉCANE ET COMPOSÉS SIMILAIRES UTILISÉS EN TANT QU'INHIBITEURS DE RÉPLICATION DE NOROVIRUS ET DE CORONAVIRUS
  申请人：COCRYSTAL PHARMA INC

  公开号：WO2021188620A1

  公开（公告）日：2021-09-23

  Peptidomimetic N5-methyl-N2-(nonanoyl-L-leucyl)-L-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds for use in methods of inhibiting the replication of noroviruses and coronaviruses in a biological sample or patient, for use in reducing the amount of noroviruses or coronaviruses in a biological sample or patient, and for use in treating norovirus and coronavirus in a patient, comprising administering to said biological sample or patient a safe and effective amount of a compound represented by formulae I or II, or a pharmaceutically acceptable salt thereof. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. page 99 to page 271; examples 1 to 3; compounds A1 to A104 and Bl to B66; tables A to E).

  肽拟态N5-甲基-N2-(壬酰基-L-亮氨酰基)-L-谷氨酸衍生物，三唑螺[4.14]十九烷衍生物以及类似化合物用于抑制生物样本或患者中诺如病毒和冠状病毒的复制，用于减少生物样本或患者中诺如病毒或冠状病毒的数量，以及用于治疗患者中的诺如病毒和冠状病毒，包括向所述生物样本或患者施用由公式I或II表示的化合物的安全有效量，或其药用可接受盐。本描述公开了典型化合物的合成和特性，以及其药理数据（例如，第99页至第271页；例1至例3；化合物A1至A104和B1至B66；表A至表E）。
• Synthesis, activity and structure–activity relationship of noroviral protease inhibitors
  作者：Lisheng Deng、Zana Muhaxhiri、Mary K. Estes、Timothy Palzkill、B. V. Venkataram Prasad、Yongcheng Song

  DOI：10.1039/c3md00219e

  日期：——

  The protease of norovirus, an important human pathogen, is essential for the viral replication and, therefore, represents a potential drug target. A series of tripeptide-based inhibitors of the protease were designed, synthesized and tested, among which several potent inhibitors were identified with Ki values as low as 75 nM. The structure–activity relationships of these inhibitors are discussed.

  诺罗病毒（一种重要的人类病原体）的蛋白酶对其复制至关重要，因此是一个潜在的药物靶点。一系列基于三肽的蛋白酶抑制剂被设计、合成并测试，其中一些强效抑制剂被鉴定出来，其Ki值低至75 nM。这些抑制剂的结构-活性关系被讨论。
• Antirheumatic Agents. III. Novel Methotrexate Derivatives Bearing an Indoline Ring and a Modified Ornithine or Glutamic Acid.
  作者：Hiroharu MATSUOKA、Nobuaki KATO、Nobuhiro OHI、Katsuhito MIYAMOTO、Masahiko MIHARA、Yasuhisa TAKEDA

  DOI：10.1248/cpb.45.1146

  日期：——

  The synthesis, biological profile and structure-activity relationship of various methotrexate (MTX) derivatives bearing an indoline ring are described. In particlular, Nδ-(3-carboxyphenyl)-Nα-[1-[(2, 4-diaminopteridin-6-yl)-methyl]indoline-5-ylcarbonyl]-L-glutamine (3d), compared to MTX, exhibited an enhanced anti-proliferative effect on human peripheral blood mononuclear cells obtained from healthy volunteers.

  描述了多种具有吲哚环的甲氨蝶呤（MTX）衍生物的合成、生物学特征及其结构-活性关系。特别是，与MTX相比，Nδ-(3-羧基苯基)-Nα-[1-[(2, 4-二氨基居普噻啶-6-基)-甲基]吲哚-5-基氨基]-L-谷氨酸（3d）在从健康志愿者获得的人外周血单核细胞上表现出增强的抗增殖效果。
• Enzyme Inhibition by Hydroamination: Design and Mechanism of a Hybrid Carmaphycin-Syringolin Enone Proteasome Inhibitor
  作者：Daniela B.B. Trivella、Alban R. Pereira、Martin L. Stein、Yusuke Kasai、Tara Byrum、Frederick A. Valeriote、Dean J. Tantillo、Michael Groll、William H. Gerwick、Bradley S. Moore

  DOI：10.1016/j.chembiol.2014.04.010

  日期：2014.6

  Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and alpha,beta-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.