[4-(2,2,2-Trifluoro-acetylamino)-phenyl]-acetic acid (1R,2R)-2-(2,2-dichloro-acetylamino)-1-(4-nitro-phenyl)-propyl ester | 165063-82-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: [4-(2,2,2-Trifluoro-acetylamino)-phenyl]-acetic acid (1R,2R)-2-(2,2-dichloro-acetylamino)-1-(4-nitro-phenyl)-propyl ester
• CAS: 165063-82-1
• 化学式: C₂₁H₁₈Cl₂F₃N₃O₆
• 分子量: 536.292
• InChiKey: TXIASYGHZDCCGR-DIFFPNOSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.23
• 重原子数：
  35.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  127.64
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  Toluene-4-sulfonic acid (2R,3R)-2-(2,2-dichloro-acetylamino)-3-hydroxy-3-(4-nitro-phenyl)-propyl ester 在 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 6.8h， 生成 [4-(2,2,2-Trifluoro-acetylamino)-phenyl]-acetic acid (1R,2R)-2-(2,2-dichloro-acetylamino)-1-(4-nitro-phenyl)-propyl ester
  参考文献：
  名称：

  Correlation between Antigen-Combining-Site Structures and Functions within a Panel of Catalytic Antibodies Generated against a Single Transition State Analog

  摘要：

  The diversity of the immune response, which can provide a panel of catalytic antibodies with varying degrees of catalytic activity and substrate specificity by immunization with a single hapten,raises the question concerning the extent to which a rationally designed hapten dictates the paratopes for catalytic function in the antigen-combining site. We have investigated the biochemical properties within a panel of six hydrolytic catalytic antibodies elicited against a phosphonate transition state analog 3 and:have examined the correlation between the functions and the antigen-combining-site structures. Although the individual values for k(cat), K-m, and K-TsA (the affinity for the transition state analog) of the six antibodies differed substantially, the transition state analysis (k(cat)/k(uncat) versus K-S/K-TSA) displayed a linear relationship (slope = 0.99) with the four antibodies 6D9, 8D11, 4D5, and 9C10, which have homologous primary amino acid sequences,providing evidence that all of the differential binding energy of the transition state vs the ground state is available for the rate enhancement. This also suggested that these four antibodies catalyze the hydrolysis by variations of the same basic mechanism of transition state stabilization. In antibody 6D9, the difference in free energy between the antibody-catalyzed and uncatalyzed reactions was calculated to be 4.0 kcal/mol, a value that is consistent with the typical binding energy for one hydrogen bond between charged and uncharged groups in enzyme-substrate complexes. On the other hand, antibody 7C8, which has an amino acid sequence different from those of the others, deviated from the linear relationship observed in the transition state analysis, suggesting that catalytic factors other than transition state stabilization, such as a functioning acid or base, are involved in the catalysis. Thus, the difference in the catalytic properties is reflected in the differences in the Fv amino acid sequences. The analysis of the substrate specificity suggested that the catalytic antibodies with highly homologous primary amino acid sequences possess homogeneous binding modes to the substrate or hapten. The three-dimensional molecular model of the antibody 6D9-hapten complex reveals that the phosphonate moiety in the hapten interacts with His (L27d), a catalytic amino acid residue participating in the transition state stabilization in the antibody-catalyzed reactions. This histidine is conserved in the catalytic antibodies 6D9, 8D11, 4B5, and 9C10, and chemical modification by DEPC treatment caused a complete loss of the hydrolytic activity. Although the amino acid sequence of antibody 3G6 is highly homologous to the other four catalytic antibodies; antibody 3G6 has Tyr (L27d), which had reduced activity when modified with tetranitromethane., It is noteworthy that the majority of these catalytic antibodies, generated against a single transition state analog, display high homology in the biochemical and structural properties and catalyze the reaction with the same mechanism expected from designing the transition state analog. These findings emphasize the critical importance of hapten affinity to transition state stabilization and of chemically designing haptens that closely resemble the true transition state for the generation of catalytic antibodies.

  DOI：

  10.1021/ja00128a006