8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-[(methoxyphenylphosphinyl)oxy]-8-methyl-, methyl ester, (1R,2R,3S,5S)-

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-[(methoxyphenylphosphinyl)oxy]-8-methyl-, methyl ester, (1R,2R,3S,5S)-
• 英文别名: methyl (1R,2R,3S,5S)-3-[methoxy(phenyl)phosphoryl]oxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• 化学式: C₁₇H₂₄NO₅P
• 分子量: 353.355
• InChiKey: FVRMCWSLWSXMTJ-FZUATOERSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-[(methoxyphenylphosphinyl)oxy]-8-methyl-, methyl ester, (1R,2R,3S,5S)- 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以90%的产率得到3-<(phenylphosphonyl)oxy>-<1R-(exo,exo)>-8-methyl-8-azabicyclo<3.2.1>octane-2-carboxylic acid methyl ester
  参考文献：
  名称：

  Anti-Cocaine Catalytic Antibodies:  A Synthetic Approach to Improved Antibody Diversity

  摘要：

  Catalytic antibodies are potential therapeutic agents for drug overdose and addiction, and we previously reported the first such artificial enzymes to degrade cocaine. However, as described herein, these catalytic monoclonal antibodies (Mab's) were found to have nearly identical complementarity-determining regions (CDR's). Such limited diversity among catalytic antibodies of similar specificity has been reported previously and poses a problem since the capacity of any single group of homologous catalytic antibodies to yield one of high activity, whether through repetitive screening of hybridomas or through antibody mutagenesis, is unpredictable. One strategy to increase the diversity of the immune response to an analog would be to vary the tether site of the immunogenic conjugate thereby exposing unique epitopes for immunorecognition. We now report the syntheses of three immunogenic conjugates of a transition-state analog (TSA) of cocaine benzoyl ester hydrolysis which have identical phosphonate monoester core structures but varying tether sites for attachment to carrier protein: TSA 1 at the methyl ester, TSA 2 at the 4'-phenyl position, and TSA 3 at the tropane nitrogen. Mixed phosphonate diester precursors were obtained from phosphonic dichlorides and ecgonine alkyl esters through our 1H-tetrazole catalysis method. We found that all three analogs provided catalytic antibodies that hydrolyze cocaine at the benzoyl ester; the most active catalytic antibody, Mab 15A10, displayed a rate acceleration (k(cat)/k(uncat) = 2.3 x 10(4)) sufficient to commence preclinical studies. On competitive ELISA, all nine catalytic antibodies, regardless of the eliciting antigen, bound TSA 1 with high affinity but four bound TSA 3 poorly and five failed to bind TSA 2 despite the inhibition of all antibodies by free TSA (TSA 4). A comparison of heavy and of light chain CDR's showed four discrete groups with TSA 1 and 3 each yielding two non-overlapping families of catalytic antibodies; TSA 2 yielded one antibody with CDR's nearly identical to those of the largest group of catalytic antibodies elicited by TSA 1. The failure of TSA 2 and TSA 3 to bind to catalytic antibodies derived from alternative immunogenic conjugates demonstrates that the tether sire does limit the catalytic antibodies produced and supports the general strategy of varying the attachment to carrier protein.

  DOI：

  10.1021/ja953077+
• 作为产物：
  描述：

  苯膦酰二氯 、 甲醇 、 芽子碱甲酯 在 四氮唑 、 N,N-二异丙基乙胺 作用下， 生成 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-[(methoxyphenylphosphinyl)oxy]-8-methyl-, methyl ester, (1R,2R,3S,5S)-
  参考文献：
  名称：

  Anti-Cocaine Catalytic Antibodies:  A Synthetic Approach to Improved Antibody Diversity

  摘要：

  Catalytic antibodies are potential therapeutic agents for drug overdose and addiction, and we previously reported the first such artificial enzymes to degrade cocaine. However, as described herein, these catalytic monoclonal antibodies (Mab's) were found to have nearly identical complementarity-determining regions (CDR's). Such limited diversity among catalytic antibodies of similar specificity has been reported previously and poses a problem since the capacity of any single group of homologous catalytic antibodies to yield one of high activity, whether through repetitive screening of hybridomas or through antibody mutagenesis, is unpredictable. One strategy to increase the diversity of the immune response to an analog would be to vary the tether site of the immunogenic conjugate thereby exposing unique epitopes for immunorecognition. We now report the syntheses of three immunogenic conjugates of a transition-state analog (TSA) of cocaine benzoyl ester hydrolysis which have identical phosphonate monoester core structures but varying tether sites for attachment to carrier protein: TSA 1 at the methyl ester, TSA 2 at the 4'-phenyl position, and TSA 3 at the tropane nitrogen. Mixed phosphonate diester precursors were obtained from phosphonic dichlorides and ecgonine alkyl esters through our 1H-tetrazole catalysis method. We found that all three analogs provided catalytic antibodies that hydrolyze cocaine at the benzoyl ester; the most active catalytic antibody, Mab 15A10, displayed a rate acceleration (k(cat)/k(uncat) = 2.3 x 10(4)) sufficient to commence preclinical studies. On competitive ELISA, all nine catalytic antibodies, regardless of the eliciting antigen, bound TSA 1 with high affinity but four bound TSA 3 poorly and five failed to bind TSA 2 despite the inhibition of all antibodies by free TSA (TSA 4). A comparison of heavy and of light chain CDR's showed four discrete groups with TSA 1 and 3 each yielding two non-overlapping families of catalytic antibodies; TSA 2 yielded one antibody with CDR's nearly identical to those of the largest group of catalytic antibodies elicited by TSA 1. The failure of TSA 2 and TSA 3 to bind to catalytic antibodies derived from alternative immunogenic conjugates demonstrates that the tether sire does limit the catalytic antibodies produced and supports the general strategy of varying the attachment to carrier protein.

  DOI：

  10.1021/ja953077+

文献信息

• Anti-Cocaine Catalytic Antibodies:  A Synthetic Approach to Improved Antibody Diversity
  作者：G. Yang、J. Chun、H. Arakawa-Uramoto、X. Wang、M. A. Gawinowicz、K. Zhao、D. W. Landry

  DOI：10.1021/ja953077+

  日期：1996.1.1

  Catalytic antibodies are potential therapeutic agents for drug overdose and addiction, and we previously reported the first such artificial enzymes to degrade cocaine. However, as described herein, these catalytic monoclonal antibodies (Mab's) were found to have nearly identical complementarity-determining regions (CDR's). Such limited diversity among catalytic antibodies of similar specificity has been reported previously and poses a problem since the capacity of any single group of homologous catalytic antibodies to yield one of high activity, whether through repetitive screening of hybridomas or through antibody mutagenesis, is unpredictable. One strategy to increase the diversity of the immune response to an analog would be to vary the tether site of the immunogenic conjugate thereby exposing unique epitopes for immunorecognition. We now report the syntheses of three immunogenic conjugates of a transition-state analog (TSA) of cocaine benzoyl ester hydrolysis which have identical phosphonate monoester core structures but varying tether sites for attachment to carrier protein: TSA 1 at the methyl ester, TSA 2 at the 4'-phenyl position, and TSA 3 at the tropane nitrogen. Mixed phosphonate diester precursors were obtained from phosphonic dichlorides and ecgonine alkyl esters through our 1H-tetrazole catalysis method. We found that all three analogs provided catalytic antibodies that hydrolyze cocaine at the benzoyl ester; the most active catalytic antibody, Mab 15A10, displayed a rate acceleration (k(cat)/k(uncat) = 2.3 x 10(4)) sufficient to commence preclinical studies. On competitive ELISA, all nine catalytic antibodies, regardless of the eliciting antigen, bound TSA 1 with high affinity but four bound TSA 3 poorly and five failed to bind TSA 2 despite the inhibition of all antibodies by free TSA (TSA 4). A comparison of heavy and of light chain CDR's showed four discrete groups with TSA 1 and 3 each yielding two non-overlapping families of catalytic antibodies; TSA 2 yielded one antibody with CDR's nearly identical to those of the largest group of catalytic antibodies elicited by TSA 1. The failure of TSA 2 and TSA 3 to bind to catalytic antibodies derived from alternative immunogenic conjugates demonstrates that the tether sire does limit the catalytic antibodies produced and supports the general strategy of varying the attachment to carrier protein.