7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester
• 英文别名: 9H-Fluoren-9-ylmethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
• 化学式: C₂₀H₁₉NO₃
• 分子量: 321.376
• InChiKey: ZZDFHQUZOCMXTK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  42.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3,6-Dihydro-2H-pyridine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester 在 碳酸氢钠 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以89%的产率得到7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester
  参考文献：
  名称：

  Irreversible Inhibition of the HIV-1 Protease:  Targeting Alkylating Agents to the Catalytic Aspartate Groups

  摘要：

  Irreversible inhibition of the HIV-1 protease by agents that specifically alkylate its catalytic aspartate residues is a potentially useful approach for circumventing the evolution of HIV strains that are resistant to protease inhibitors. Five haloperidol- and two FMOC-based epoxides of differing reactivities have been synthesized and tested as irreversible inhibitors of the HIV-1 protease (HIV-1 PR). Of these, two trisubstituted epoxides, a cis-1,2- disubstituted epoxide, a 1,1-disubstituted epoxide, and a monosubstituted epoxide function as irreversible inhibitors, but two trans-1,2-disubstituted epoxides do not. The most effective of the epoxides (6) inactivates HIV-1 PR with K-inact = 65 mu M and V-inact = 0.009 min(-1). 1,2-Epoxy-3-(p-nitrophenoxy)propane (EPNP), a nonspecific inactivating agent for aspartyl proteases, has been used to validate a protocol for establishing the stoichiometry and site of protein alkylation. Mass spectrometric analysis of the inactivated enzyme shows that one molecule of either EPNP or the cyclic 1,2-disubstituted epoxide 6 is covalently bound per HIV-1 PR dimer. Mass spectrometric sequencing of labeled proteolytic peptides shows that both inhibitors are covalently bound to a catalytic aspartate residue. The covalent binding of three alpha,beta-unsaturated ketone derivatives of haloperidol has been similarly examined. Analysis of HIV-1 PR inactivated by these agents establishes that they bind covalently to the two cysteines and the N-terminal amino group but not detectably to the catalytic aspartate residues. The results indicate that aspartate-targeted inactivation of HIV-1 PR depends on (a) matching the reactivity of the alkylating functionality to that of the aspartates, preferably by exploiting the two-aspartate catalytic motif of the protease to activate the alkylating agent, and (b) appropriate positioning of the alkylating functionality within the active site. These requirements are readily met by a monosubstituted, 1,1-disubstituted, or cyclic cis-1,2-disubstituted epoxide but not by trans-1,2-disubstituted epoxides or alpha,beta-unsaturated ketones.

  DOI：

  10.1021/ja954069w

文献信息

• Irreversible Inhibition of the HIV-1 Protease:  Targeting Alkylating Agents to the Catalytic Aspartate Groups
  作者：Zhonghua Yu、Patricia Caldera、Fiona McPhee、James J. De Voss、Patrick R. Jones、Alma L. Burlingame、Irwin D. Kuntz、Charles S. Craik、Paul R. Ortiz de Montellano

  DOI：10.1021/ja954069w

  日期：1996.1.1

  Irreversible inhibition of the HIV-1 protease by agents that specifically alkylate its catalytic aspartate residues is a potentially useful approach for circumventing the evolution of HIV strains that are resistant to protease inhibitors. Five haloperidol- and two FMOC-based epoxides of differing reactivities have been synthesized and tested as irreversible inhibitors of the HIV-1 protease (HIV-1 PR). Of these, two trisubstituted epoxides, a cis-1,2- disubstituted epoxide, a 1,1-disubstituted epoxide, and a monosubstituted epoxide function as irreversible inhibitors, but two trans-1,2-disubstituted epoxides do not. The most effective of the epoxides (6) inactivates HIV-1 PR with K-inact = 65 mu M and V-inact = 0.009 min(-1). 1,2-Epoxy-3-(p-nitrophenoxy)propane (EPNP), a nonspecific inactivating agent for aspartyl proteases, has been used to validate a protocol for establishing the stoichiometry and site of protein alkylation. Mass spectrometric analysis of the inactivated enzyme shows that one molecule of either EPNP or the cyclic 1,2-disubstituted epoxide 6 is covalently bound per HIV-1 PR dimer. Mass spectrometric sequencing of labeled proteolytic peptides shows that both inhibitors are covalently bound to a catalytic aspartate residue. The covalent binding of three alpha,beta-unsaturated ketone derivatives of haloperidol has been similarly examined. Analysis of HIV-1 PR inactivated by these agents establishes that they bind covalently to the two cysteines and the N-terminal amino group but not detectably to the catalytic aspartate residues. The results indicate that aspartate-targeted inactivation of HIV-1 PR depends on (a) matching the reactivity of the alkylating functionality to that of the aspartates, preferably by exploiting the two-aspartate catalytic motif of the protease to activate the alkylating agent, and (b) appropriate positioning of the alkylating functionality within the active site. These requirements are readily met by a monosubstituted, 1,1-disubstituted, or cyclic cis-1,2-disubstituted epoxide but not by trans-1,2-disubstituted epoxides or alpha,beta-unsaturated ketones.