(3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone | 204919-48-2

• 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: (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone
• CAS: 204919-48-2
• 化学式: C₁₅H₂₉N₅O₄
• 分子量: 343.426
• InChiKey: IDYXVJMBSJEQSF-QWRGUYRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.23
• 重原子数：
  24.0
• 可旋转键数：
  8.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  148.9
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Ac-tLeu-Asp-H is the minimal and highly effective human caspase-3 inhibitor: biological and in silico studies

  摘要：

  Caspase-3 displays a pivotal role as an executioner of apoptosis, hydrolyzing several proteins including the nuclear enzyme poly(ADP-ribose)polymerase (PARP). Ac-Asp-Glu-Val-Asp-H (K (i)A degrees A = 2.3 x 10(-10) M at pH 7.5 and 25.0 A degrees C), designed on the basis of the cleavage site of PARP, has been reported as a highly specific human caspase-3 inhibitor. Here, di- and tri-peptidyl aldehydes 11-13 and 27-29 have been synthesized to overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of the current inhibitors. Compounds 11-13, 27-29 inhibit in vitro human caspase-3 competitively, values of K (i)A degrees ranging between 6.5 (+/- 0.82) x 10(-9) M and 1.1 (+/- 0.04) x 10(-7) M (at pH 7.4 and 25.0 A degrees C). Moreover, the most effective caspase-3 inhibitor 11 impairs apoptosis in human DLD-1 colon adenocarcinoma cells. Furthermore, the binding mode of 11-13 and 27-29 to human caspase-3 has been investigated in silico. The comparative analysis of human caspase-3 inhibitors indicates that (1) aldehyde 11 is the minimal highly effective inhibitor, (2) the tLeu-Asp sequence is pivotal for satisfactory enzyme inhibition, and (3) the occurrence of the tLeu residue at the inhibitor P2 position is fundamental for enzyme/inhibitor recognition. Moreover, calculations suggest that the tLeu residue reduces the conformational flexibility of the inhibitor that binds to the enzyme with a lower energetic penalty.

  DOI：

  10.1007/s00726-014-1855-3
• 作为产物：
  描述：

  在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 为溶剂， 反应 0.33h， 生成 (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone
  参考文献：
  名称：

  Ac-tLeu-Asp-H is the minimal and highly effective human caspase-3 inhibitor: biological and in silico studies

  摘要：

  Caspase-3 displays a pivotal role as an executioner of apoptosis, hydrolyzing several proteins including the nuclear enzyme poly(ADP-ribose)polymerase (PARP). Ac-Asp-Glu-Val-Asp-H (K (i)A degrees A = 2.3 x 10(-10) M at pH 7.5 and 25.0 A degrees C), designed on the basis of the cleavage site of PARP, has been reported as a highly specific human caspase-3 inhibitor. Here, di- and tri-peptidyl aldehydes 11-13 and 27-29 have been synthesized to overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of the current inhibitors. Compounds 11-13, 27-29 inhibit in vitro human caspase-3 competitively, values of K (i)A degrees ranging between 6.5 (+/- 0.82) x 10(-9) M and 1.1 (+/- 0.04) x 10(-7) M (at pH 7.4 and 25.0 A degrees C). Moreover, the most effective caspase-3 inhibitor 11 impairs apoptosis in human DLD-1 colon adenocarcinoma cells. Furthermore, the binding mode of 11-13 and 27-29 to human caspase-3 has been investigated in silico. The comparative analysis of human caspase-3 inhibitors indicates that (1) aldehyde 11 is the minimal highly effective inhibitor, (2) the tLeu-Asp sequence is pivotal for satisfactory enzyme inhibition, and (3) the occurrence of the tLeu residue at the inhibitor P2 position is fundamental for enzyme/inhibitor recognition. Moreover, calculations suggest that the tLeu residue reduces the conformational flexibility of the inhibitor that binds to the enzyme with a lower energetic penalty.

  DOI：

  10.1007/s00726-014-1855-3