(2S,3S)-3-<amino>-2-hydroxy-4-phenyl-1-(N-prolylisoleucylvaline methyl ester)butane | 132234-32-3

• 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: (2S,3S)-3-<amino>-2-hydroxy-4-phenyl-1-(N-prolylisoleucylvaline methyl ester)butane
• 英文别名: methyl (2S)-2-[[(2S,3S)-2-[[(2S)-1-[(2S,3S)-3-[[(2S)-4-amino-2-(tert-butoxycarbonylamino)-4-oxo-butanoyl]amino]-2-hydroxy-4-phenyl-butyl]pyrrolidine-2-carbonyl]amino]-3-methyl-pentanoyl]amino]-3-methyl-butanoate；methyl (2S)-2-[[(2S,3S)-2-[[(2S)-1-[(2S,3S)-3-[[(2S)-4-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoyl]amino]-2-hydroxy-4-phenylbutyl]pyrrolidine-2-carbonyl]amino]-3-methylpentanoyl]amino]-3-methylbutanoate
• CAS: 132234-32-3；132339-14-1
• 化学式: C₃₆H₅₈N₆O₉
• 分子量: 718.891
• InChiKey: SLLLAIADHHHUAB-KNWHVVHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  51
• 可旋转键数：
  21
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  219
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-<amino>-2-hydroxy-4-phenyl-1-(N-prolylisoleucylvaline methyl ester)butane 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.67h， 生成 (2S,3S)-3-<(N-acetyl-O-benzylserinylleucinylasparaginyl)amino>-2-hydroxy-4-phenyl-1-(N-prolylisoleucylvaline methyl ester)butane
  参考文献：
  名称：

  New hydroxyethylamine HIV protease inhibitors that suppress viral replication

  摘要：

  The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with K(i) values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEMX174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cell (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 mug/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.

  DOI：

  10.1021/jm00099a008
• 作为产物：
  描述：

  ((S)-1-benzylallyl)carbamic acid tert-butyl ester 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 异丙醚 为溶剂， 反应 27.67h， 生成 (2S,3S)-3-<amino>-2-hydroxy-4-phenyl-1-(N-prolylisoleucylvaline methyl ester)butane
  参考文献：
  名称：

  New hydroxyethylamine HIV protease inhibitors that suppress viral replication

  摘要：

  The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with K(i) values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEMX174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cell (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 mug/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.

  DOI：

  10.1021/jm00099a008

文献信息

• Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes
  作者：Daniel H. Rich、Chong Qing Sun、J. V. N. Vara Prasad、Ahammadunny Pathiasseril、Mihaly V. Toth、Garland R. Marshall、Michael Clare、Richard A. Mueller、Kathryn Houseman

  DOI：10.1021/jm00107a049

  日期：1991.3
• RICH, DANIEL H.;SUA, CHONG QING;PRASAD, J. V. N. VARA;PATHIASSERIL, AHAMM+, J. MED. CHEM., 34,(1991) N, C. 1222-1225
  作者：RICH, DANIEL H.、SUA, CHONG QING、PRASAD, J. V. N. VARA、PATHIASSERIL, AHAMM+

  DOI：——

  日期：——
• New hydroxyethylamine HIV protease inhibitors that suppress viral replication
  作者：Daniel H. Rich、J. V. N. Vara Prasad、Chong Qing Sun、Jeremy Green、Richard Mueller、Kathryn Houseman、Debra MacKenzie、Miroslav Malkovsky

  DOI：10.1021/jm00099a008

  日期：1992.10

  The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with K(i) values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEMX174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cell (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 mug/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.