H-Thr-Pro-Leu-NH2 | 365276-03-5

• 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: H-Thr-Pro-Leu-NH2
• 英文别名: (2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]-N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide
• CAS: 365276-03-5
• 化学式: C₁₅H₂₈N₄O₄
• 分子量: 328.412
• InChiKey: UOSOFSZFYRJFNL-RHYQMDGZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  139
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,3R)-3-(((S)-1-(((S)-1-((S)-2-((S)-2-(((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-3-hydroxy-1-oxopropan-2-yl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamoyl)oxirane-2-carboxylic acid 、 H-Thr-Pro-Leu-NH2 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Probing of primed and unprimed sites of calpains: Design, synthesis and evaluation of epoxysuccinyl-peptide derivatives as selective inhibitors

  摘要：

  Calpains are intracellular cysteine proteases with important physiological functions. Up- or down-regulation of their expression can be responsible for several diseases, therefore specific calpain inhibitors may be considered as promising candidates for drug discovery. In this paper we describe the synthesis and characterization of a new class of inhibitors derived from the analysis of amino acid preferences in primed and unprimed sites of calpains by incorporation of L- or D-epoxysuccinyl group (Eps). Amino acids for replacement were chosen by considering the substrate preference of calpain 1 and 2 enzymes. The compounds were characterized by RP-HPLC, amino acid analysis and ESI-MS. Selectivity of the compounds was studied by using calpain 1 and 2; and cathepsin B. We have identified five calpain specific inhibitors with different extent of selectivity. Two of these also exhibited isoform selectivity. Compound NH2-Thr-Pro-Leu-(D-Eps)-Thr-Pro-Pro-Pro-Ser-NH2 proved to be a calpain 2 enzyme inhibitor with at least 11.8-fold selectivity, while compound NH2-Thr-Pro-Leu-(L-Eps)-Ser-Pro-Pro-Pro-Ser-NH2 possesses calpain 1 enzyme inhibition with at least 4-fold selectivity. The results of molecular modeling calculations suggest that the orientation of the bound inhibitor in the substrate binding cleft is markedly dependent on the stereochemistry of the epoxysuccinyl group. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.05.058
• 作为产物：
  描述：

  Fmoc-Thr(tBu)-Resin 、 L-亮氨酸 、 L-脯氨酸 在 哌啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 H-Thr-Pro-Leu-NH2
  参考文献：
  名称：

  Probing of primed and unprimed sites of calpains: Design, synthesis and evaluation of epoxysuccinyl-peptide derivatives as selective inhibitors

  摘要：

  Calpains are intracellular cysteine proteases with important physiological functions. Up- or down-regulation of their expression can be responsible for several diseases, therefore specific calpain inhibitors may be considered as promising candidates for drug discovery. In this paper we describe the synthesis and characterization of a new class of inhibitors derived from the analysis of amino acid preferences in primed and unprimed sites of calpains by incorporation of L- or D-epoxysuccinyl group (Eps). Amino acids for replacement were chosen by considering the substrate preference of calpain 1 and 2 enzymes. The compounds were characterized by RP-HPLC, amino acid analysis and ESI-MS. Selectivity of the compounds was studied by using calpain 1 and 2; and cathepsin B. We have identified five calpain specific inhibitors with different extent of selectivity. Two of these also exhibited isoform selectivity. Compound NH2-Thr-Pro-Leu-(D-Eps)-Thr-Pro-Pro-Pro-Ser-NH2 proved to be a calpain 2 enzyme inhibitor with at least 11.8-fold selectivity, while compound NH2-Thr-Pro-Leu-(L-Eps)-Ser-Pro-Pro-Pro-Ser-NH2 possesses calpain 1 enzyme inhibition with at least 4-fold selectivity. The results of molecular modeling calculations suggest that the orientation of the bound inhibitor in the substrate binding cleft is markedly dependent on the stereochemistry of the epoxysuccinyl group. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.05.058

文献信息

• Probing of primed and unprimed sites of calpains: Design, synthesis and evaluation of epoxysuccinyl-peptide derivatives as selective inhibitors
  作者：Levente E. Dókus、Dóra K. Menyhárd、Ágnes Tantos、Ferenc Hudecz、Zoltán Bánóczi

  DOI：10.1016/j.ejmech.2014.05.058

  日期：2014.7

  Calpains are intracellular cysteine proteases with important physiological functions. Up- or down-regulation of their expression can be responsible for several diseases, therefore specific calpain inhibitors may be considered as promising candidates for drug discovery. In this paper we describe the synthesis and characterization of a new class of inhibitors derived from the analysis of amino acid preferences in primed and unprimed sites of calpains by incorporation of L- or D-epoxysuccinyl group (Eps). Amino acids for replacement were chosen by considering the substrate preference of calpain 1 and 2 enzymes. The compounds were characterized by RP-HPLC, amino acid analysis and ESI-MS. Selectivity of the compounds was studied by using calpain 1 and 2; and cathepsin B. We have identified five calpain specific inhibitors with different extent of selectivity. Two of these also exhibited isoform selectivity. Compound NH2-Thr-Pro-Leu-(D-Eps)-Thr-Pro-Pro-Pro-Ser-NH2 proved to be a calpain 2 enzyme inhibitor with at least 11.8-fold selectivity, while compound NH2-Thr-Pro-Leu-(L-Eps)-Ser-Pro-Pro-Pro-Ser-NH2 possesses calpain 1 enzyme inhibition with at least 4-fold selectivity. The results of molecular modeling calculations suggest that the orientation of the bound inhibitor in the substrate binding cleft is markedly dependent on the stereochemistry of the epoxysuccinyl group. (C) 2014 Elsevier Masson SAS. All rights reserved.