N-((2S,3S)-3-trans-ethoxycarbonyloxiran-2-carbonyl)-L-phenylalanine benzyl amide | 159086-41-6

• 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: N-((2S,3S)-3-trans-ethoxycarbonyloxiran-2-carbonyl)-L-phenylalanine benzyl amide
• CAS: 159086-41-6
• 化学式: C₂₂H₂₄N₂O₅
• 分子量: 396.443
• InChiKey: XSQNJWIYYFZIPY-FHWLQOOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.36
• 重原子数：
  29.0
• 可旋转键数：
  9.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  97.03
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-((2S,3S)-3-trans-ethoxycarbonyloxiran-2-carbonyl)-L-phenylalanine benzyl amide 在 phosphate buffer 作用下， 以 乙腈 为溶剂， 以48%的产率得到N-((2S,3S)-3-trans-hydroxycarbonyloxiran-2-carbonyl)-L-phenylalanine benzyl amide
  参考文献：
  名称：

  E-64 Analogs as Inhibitors of Cathepsin L and Cathepsin S: Importance of the S2-P2 Interactions for Potency and Selectivity1

  摘要：

  A number of epoxysuccinyl amino acid benzyl esters (HO-Eps-AA-OBzl, 1) in which the amino acid (AA) had been systematically varied were tested as inhibitors of cathepsins 1, and S. These E-64 analogs were designed to investigate whether selectivity for cathepsin 1, or cathepsin S could be attained by varying the amino acid bound to the essential epoxide ring which induces inhibition by alkylating the active site thiol of the cysteine proteases. The results indicate that the specificity of these analogs does not parallel that observed for substrates. This is possibly due to the fact that the direction of the peptide portion of these analogs, which is the reverse of that found for the substrate-like chloromethyl ketones (if the situation is analogous to papain), leads to differences in the orientation of the inhibitor side chain when bound in the SZ subsite compared to substrates. The greatest selectivity was obtained with HO-Eps-Arg-OBzl which exhibited an 89-fold preference for cathepsin 1, over cathepsin S. A change from the L to the D stereochemistry for the phenylalanine analogs resulted in a 19-fold drop in k(2)/K-i for cathepsin L and a 14-fold drop for cathepsin S. Both E-64 and Cbz-Phe-Ala-CH2Cl form two hydrogen bonds with Gly 66 in the active site of papain. With the benzyl esters (HO-Eps-AA-OBzl) one of these hydrogen bonds is necessarily absent. In order to evaluate the importance of this hydrogen bond, three benzyl amide derivatives (HO-Eps-AA-NHBzl, 2) were synthesized. In all cases the potency of the inhibitor was increased and indeed the HO-Eps-Phe-NHBzl analog is 64-fold more potent than the corresponding benzyl ester. For cathepsin L, there is also a 237-fold preference for L-Phe over D-Phe in the benzyl amide analog. In conclusion, although the information available from S-2-P-2 interactions with substrates cannot be used to enhance the selectivity of the E-64 I analogs in a rational manner, the hydrogen-bonding interaction between the amide proton of the benzyl amid group in HO-Eps-AA-NHBzl and the S-2 subsite for both cathepsins L and S contributes to increase the potency of these types of inhibitors.

  DOI：

  10.1006/bioo.1994.1017
• 作为产物：
  描述：

  二乙基 (2S,3S)-(+)-2,3-环氧琥珀酸 在 sodium hydroxide 、 potassium dihydrogenphosphate 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 反应 1.5h， 生成 N-((2S,3S)-3-trans-ethoxycarbonyloxiran-2-carbonyl)-L-phenylalanine benzyl amide
  参考文献：
  名称：

  E-64 Analogs as Inhibitors of Cathepsin L and Cathepsin S: Importance of the S2-P2 Interactions for Potency and Selectivity1

  摘要：

  A number of epoxysuccinyl amino acid benzyl esters (HO-Eps-AA-OBzl, 1) in which the amino acid (AA) had been systematically varied were tested as inhibitors of cathepsins 1, and S. These E-64 analogs were designed to investigate whether selectivity for cathepsin 1, or cathepsin S could be attained by varying the amino acid bound to the essential epoxide ring which induces inhibition by alkylating the active site thiol of the cysteine proteases. The results indicate that the specificity of these analogs does not parallel that observed for substrates. This is possibly due to the fact that the direction of the peptide portion of these analogs, which is the reverse of that found for the substrate-like chloromethyl ketones (if the situation is analogous to papain), leads to differences in the orientation of the inhibitor side chain when bound in the SZ subsite compared to substrates. The greatest selectivity was obtained with HO-Eps-Arg-OBzl which exhibited an 89-fold preference for cathepsin 1, over cathepsin S. A change from the L to the D stereochemistry for the phenylalanine analogs resulted in a 19-fold drop in k(2)/K-i for cathepsin L and a 14-fold drop for cathepsin S. Both E-64 and Cbz-Phe-Ala-CH2Cl form two hydrogen bonds with Gly 66 in the active site of papain. With the benzyl esters (HO-Eps-AA-OBzl) one of these hydrogen bonds is necessarily absent. In order to evaluate the importance of this hydrogen bond, three benzyl amide derivatives (HO-Eps-AA-NHBzl, 2) were synthesized. In all cases the potency of the inhibitor was increased and indeed the HO-Eps-Phe-NHBzl analog is 64-fold more potent than the corresponding benzyl ester. For cathepsin L, there is also a 237-fold preference for L-Phe over D-Phe in the benzyl amide analog. In conclusion, although the information available from S-2-P-2 interactions with substrates cannot be used to enhance the selectivity of the E-64 I analogs in a rational manner, the hydrogen-bonding interaction between the amide proton of the benzyl amid group in HO-Eps-AA-NHBzl and the S-2 subsite for both cathepsins L and S contributes to increase the potency of these types of inhibitors.

  DOI：

  10.1006/bioo.1994.1017