3(S)-3-amino-2(RS)-hydroxy-N-phenethyl-4-phenylbutanamide | 316830-81-6

• 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: 3(S)-3-amino-2(RS)-hydroxy-N-phenethyl-4-phenylbutanamide
• 英文别名: (3S)-3-amino-2-hydroxy-4-phenyl-N-(2-phenylethyl)butanamide
• CAS: 316830-81-6
• 化学式: C₁₈H₂₂N₂O₂
• 分子量: 298.385
• InChiKey: NVDRKQATJLVEDF-BHWOMJMDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  75.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3(S)-3-amino-2(RS)-hydroxy-N-phenethyl-4-phenylbutanamide 在 N-甲基吗啉 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2R)-N-[3,4-dioxo-1-phenyl-4-(2-phenylethylamino)butan-2-yl]-1-(4-methoxyphenyl)sulfonylpyrrolidine-2-carboxamide
  参考文献：
  名称：

  Synthesis, Calpain Inhibitory Activity, and Cytotoxicity of P₂-Substituted Proline and Thiaproline Peptidyl Aldehydes and Peptidyl α-Ketoamides

  摘要：

  Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the mu-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl alpha-ketoamides with N-substituted D-proline or L-thiaproline residues at the P-2-postion. The most potent and most selective members of the series were (R)-1-(4-nitrophenylsulfonyl)-N-((R, S)-1-oxo- 3-phenylpropan-2-yl) pyrrolidine-2-carboxamide (1j) and (R)-1-(4-iodophenylsulfonyl)-N-((R,S)-1-oxo-3- phenylpropan-2-yl) pyrrolidine-2-carboxamide (1n). The compounds inhibited A-calpain with K-i values of 0.02 mu M and 0.03 mu M, respectively, and displayed over 180-fold (1j) and 130-fold ( 1n) greater affinity for mu-calpain compared to cathepsin B. The cytotoxic effect of the compounds was evaluated in two leukemia cell lines (Daudi and Jurkat) and three solid tumor cell lines (DU-145, PC-3, and HeLa). Generally the compounds were modestly cytotoxic and displayed no correlation between the cytotoxic activity and mu-calpain inhibition.

  DOI：

  10.1021/jm050849w
• 作为产物：
  描述：

  BOC-PHE-甲氧基甲胺 在 盐酸 、 sodium hydroxide 、 lithium aluminium tetrahydride 、 1-羟基苯并三唑 、 sodium hydrogensulfite 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 1,4-二氧六环 为溶剂， 生成 3(S)-3-amino-2(RS)-hydroxy-N-phenethyl-4-phenylbutanamide
  参考文献：
  名称：

  Significance of Hydrogen Bonding at the S1′ Subsite of Calpain I

  摘要：

  alpha -Ketohydroxamates were synthesized as bioisosteres of alpha -ketoamides. The alpha -ketohydroxamates were generally more potent than the corresponding alpha -ketoamides. The potency of the compounds suggests that hydrogen bonding and steric bulk of substituents on the nitrogen atom of the ketoamide moiety influence calpain inhibition. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00301-8

文献信息

• Design and synthesis of 4-aryl-4-oxobutanoic acid amides as calpain inhibitors
  作者：Yong Zhang、Seo Yoon Jung、Changbae Jin、Nam Doo Kim、Ping Gong、Yong Sup Lee

  DOI：10.1016/j.bmcl.2008.11.030

  日期：2009.1

  The involvement of mu-calpain in neurological disorders, such as stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 4-Aryl-4-oxobutanoic acid amide derivatives 4 were designed as acyclic variants of mu-calpain inhibitory chromone and quinolinone derivatives. Of the compounds synthesized, 4c-2, which possesses a 2-methoxymethoxy group at the phenyl ring and a primary amide at the warhead region most potently inhibited mu-calpain (IC50 = 0.34 mu M). Our findings suggest that the 4-aryl-4-oxobutanoic acid amide derivatives should be considered as a new family of mu-calpain inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and calpain inhibitory activity of α-ketoamides with 2,3-methanoleucine stereoisomers at the P2 position
  作者：Isaac O Donkor、Xiaozhang Zheng、Duane D Miller

  DOI：10.1016/s0960-894x(00)00518-7

  日期：2000.11

  A series of novel ketoamides incorporating all four 2,3-methanoleucine stereoisomers at the P-2 position was synthesized. The compounds displayed a wide variation in K-i values for inhibition of calpain I depending on the configuration of the P-2 methanoleucine residue. However, similar variation in cathepsin B inhibition was not observed suggesting that the S-2 pocket of calpain I is more stereosensitive than that of cathepsin B. (C) 2000 Published by Elsevier Science Ltd.
• Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives
  作者：Ki Yong Lee、Kwang Seob Lee、Changbae Jin、Yong Sup Lee

  DOI：10.1016/j.ejmech.2008.02.023

  日期：2009.3

  Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of mu-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic mu-calpain inhibitor, MDL 28,170, and their mu-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited mu-calpain with an IC50 value of 2.81 +/- 1.26 mu M, which is ca. 40-fold less than that of MDL 28,170. (C) 2008 Elsevier Masson SAS. All rights reserved.
• Significance of Hydrogen Bonding at the S1′ Subsite of Calpain I
  作者：Isaac O. Donkor、Xiaozhang Zheng、Jie Han、Calvin Lacy、Duane D. Miller

  DOI：10.1016/s0960-894x(01)00301-8

  日期：2001.7

  alpha -Ketohydroxamates were synthesized as bioisosteres of alpha -ketoamides. The alpha -ketohydroxamates were generally more potent than the corresponding alpha -ketoamides. The potency of the compounds suggests that hydrogen bonding and steric bulk of substituents on the nitrogen atom of the ketoamide moiety influence calpain inhibition. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Synthesis, Calpain Inhibitory Activity, and Cytotoxicity of P₂-Substituted Proline and Thiaproline Peptidyl Aldehydes and Peptidyl α-Ketoamides
  作者：Rajani Korukonda、Na Guan、James T. Dalton、Jiuyu Liu、Isaac O. Donkor

  DOI：10.1021/jm050849w

  日期：2006.8.1

  Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the mu-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl alpha-ketoamides with N-substituted D-proline or L-thiaproline residues at the P-2-postion. The most potent and most selective members of the series were (R)-1-(4-nitrophenylsulfonyl)-N-((R, S)-1-oxo- 3-phenylpropan-2-yl) pyrrolidine-2-carboxamide (1j) and (R)-1-(4-iodophenylsulfonyl)-N-((R,S)-1-oxo-3- phenylpropan-2-yl) pyrrolidine-2-carboxamide (1n). The compounds inhibited A-calpain with K-i values of 0.02 mu M and 0.03 mu M, respectively, and displayed over 180-fold (1j) and 130-fold ( 1n) greater affinity for mu-calpain compared to cathepsin B. The cytotoxic effect of the compounds was evaluated in two leukemia cell lines (Daudi and Jurkat) and three solid tumor cell lines (DU-145, PC-3, and HeLa). Generally the compounds were modestly cytotoxic and displayed no correlation between the cytotoxic activity and mu-calpain inhibition.