tert-butyl 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate | 1579223-89-4

• 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: tert-butyl 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate
• 英文别名: tert-butyl N-[(2S)-1-[2-(2,5-dioxopyrrol-1-yl)ethylamino]-1-oxo-3-phenylpropan-2-yl]carbamate
• CAS: 1579223-89-4
• 化学式: C₂₀H₂₅N₃O₅
• 分子量: 387.436
• InChiKey: VXZPBKXXNDNKAR-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  BOC-L-苯丙氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 19.5h， 生成 tert-butyl 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate
  参考文献：
  名称：

  Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation

  摘要：

  Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen Ala as the model kinase for this work. Using the AKT-GSK3 beta cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.

  DOI：

  10.1021/ml500088x

文献信息

• NOVEL REACTIVE ALGINIC ACID DERIVATIVES
  申请人：Mochida Pharmaceutical Co., Ltd.

  公开号：EP3778653A1

  公开（公告）日：2021-02-17

  The present invention provides alginic acid derivatives having a group represented by general formula (I) or general formula (II) (the right side of the dashed line is excluded in each formula) at a portion of the carboxyl groups in an alginic acid. Novel alginic acid derivatives are thereby provided.

  本发明提供的海藻酸衍生物在海藻酸的部分羧基上具有通式(I)或通式(II)所代表的基团（各式中均不包括虚线右侧）。由此提供了新型藻酸衍生物。
• Reactive alginic acid derivatives
  申请人：MOCHIDA PHARMACEUTICAL CO., LTD.

  公开号：US11472892B2

  公开（公告）日：2022-10-18

  The present invention provides alginic acid derivatives having a group represented by general formula (I) or general formula (II) (the right side of the dashed line is excluded in each formula) at a portion of the carboxyl groups in an alginic acid. Novel alginic acid derivatives are thereby provided.

  本发明提供的海藻酸衍生物在海藻酸的部分羧基上具有通式(I)或通式(II)所代表的基团（各式中均不包括虚线右侧）。由此提供了新型藻酸衍生物。
• NOVEL CROSSLINKED ALGINIC ACID STRUCTURE
  申请人：MOCHIDA PHARMACEUTICAL CO., LTD.

  公开号：US20220396643A1

  公开（公告）日：2022-12-15

  Provided are a novel crosslinked alginic acid, a crosslinked alginic acid structure, etc., by performing a crosslinking reaction using alginic acid derivatives represented by formula (I) and formula (II). As a result, a novel crosslinked alginic acid, crosslinked alginic acid structure, etc., are provided.
• [EN] NOVEL CROSSLINKED ALGINIC ACID STRUCTURE<br/>[FR] NOUVELLE STRUCTURE D'ACIDE ALGINIQUE RÉTICULÉ<br/>[JA] 新規な架橋アルギン酸構造体
  申请人：MOCHIDA PHARM CO LTD

  公开号：WO2021060336A1

  公开（公告）日：2021-04-01

  下記式（Ｉ）及び下記式（ＩＩ）で表されるアルギン酸誘導体を用いて架橋反応を施すことにより、新たな架橋アルギン酸、架橋アルギン酸構造体などが提供される。これにより新たな架橋アルギン酸、架橋アルギン酸構造体などが提供される。
• Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation
  作者：Thuy Nguyen、Robert A. Coover、Jenson Verghese、Richard G. Moran、Keith C. Ellis

  DOI：10.1021/ml500088x

  日期：2014.5.8

  Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen Ala as the model kinase for this work. Using the AKT-GSK3 beta cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.