PheΨProOH | 133673-22-0

• 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: PheΨProOH
• 英文别名: PheΨ(CH2N)ProOH；(2S)-1-[(2S)-2-amino-3-phenylpropyl]pyrrolidine-2-carboxylic acid
• CAS: 133673-22-0
• 化学式: C₁₄H₂₀N₂O₂
• 分子量: 248.325
• InChiKey: BPRGWUHAKOPECQ-STQMWFEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  66.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  L-脯氨酸苄酯盐酸盐 在 palladium on activated charcoal 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 、 diborane(6) 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 29.0h， 生成 PheΨProOH
  参考文献：
  名称：

  Development of methodology for the synthesis of stereochemically pure Phe.psi.[CH2N]Pro linkages in HIV protease inhibitors

  摘要：

  One of the strategies currently being pursued for the design of potential HIV protease inhibitors involves the replacement of the cleaved amide bond in a minimum peptide substrate with an aminomethylene unit. A commonly used method for the synthesis of these compounds involves a reductive alkylation of an amine with an aldehyde in the presence of sodium cyanoborohydride under acidic conditions. Accordingly, BOC-phenylalaninal (4) was reacted with the peptide-resin ProIleSer(OBzl)OResin (5) in the presence of acetic acid and sodium cyanoborohydride. The resulting product was found to consist of a mixture of diastereomers, which may result from the fact that the proline residue, which contains a secondary amine, reacts with the aldehyde to form an enamine 9 with loss of chirality at the modified Phe residue. Subsequent reduction of the iminium ion 10 would then result in production of the observed two diastereomers. In order to circumvent this problem, BOCPheProOBzl (12b) was synthesized and the central amide bond was reduced selectively with diborane. Hydrogenolysis of the benzyl protecting group gave BOCPhe-PSI[CH2N]Pro (14a), which was coupled manually to the peptide resin IleSer(OBzl)OResin to give BOCPhe-PSI[CH2N]ProIleSer(OBzl)OResin (6). Subsequent addition of amino acid residues to 6 and cleavage from the resin gave a series of stereochemically defined potential HIV protease inhibitors as single diastereomers. The most potent of these substances was ThrLeuAsnPhe-PSI[CH2N]ProIleSer (1), which displayed an IC50 of 1.1-mu-g/mL (1.4-mu-M) when tested for inhibition of HIV-1 protease. However, the epimer of 1 having the opposite configuration at the reduced Phe residue was inactive. A minimum length of seven amino acid residues appears to be necessary for effective recognition of the inhibitor by the enzyme. Further increase in chain length did not result in greater inhibitory potency.

  DOI：

  10.1021/jo00013a017

文献信息

• Verwendung von Peptidisosteren als retrovirale Proteasehemmer
  申请人：CIBA-GEIGY AG

  公开号：EP0374097A2

  公开（公告）日：1990-06-20

  Die Erfindung betrifft die Verwendung von Verbindungen vom Typus der Renininhibitoren oder verwandter Aspartatproteinaseinhibitoren als gag-Protease-Inhibitoren. Sie betrifft insbesondere die Verwendung dieser Verbindungen zur Herstellung von pharmazeutischen Präparaten zur Anwendung als gag-Protease-Hemmer, wobei Verbindunaen der Formel worin AAN ein bivalentes Radikal bestehend aus einem bis fünf bivalenten a-Aminosäureresten bedeutet, welches N-terminal mit dem Rest R2 und C-terminal mit dem Radikal Q verbunden ist, AAC eine Bindung oder ein bivalentes Radikal bestehend aus einem bis fünf bivalenten a-Aminosäureresten bedeutet, welches N-terminal mit dem Radikal Q und C-terminal mit dem Rest R1 verbunden ist, R1 für Hydroxy, verethertes Hydroxy, Amino oder substituiertes Amino mit Ausnahme eines von einer a-Aminosäure abgeleiteten Aminorestes bedeutet, R2 Wasserstoff oder einen Acylrest mit Ausnahme eines gegebenenfalls N-substituierten Acylrestes einer natürlichen Aminosäure bedeutet, und Q einen bivalenten Rest bedeutet, der ein Isoster eines Dipeptides ist, sowie Salze davon verwendet werden.

  本发明涉及肾素抑制剂或相关天冬氨酸蛋白酶抑制剂类型的化合物作为 gag 蛋白酶抑制剂的用途。特别是，本发明涉及使用这些化合物制备用作 gag 蛋白酶抑制剂的药物组合物，其中式中的化合物 其中 AAN 表示由 1 至 5 个二价 a-氨基酸残基组成的二价基，该二价基 N 端与基 R2 连接，C 端与基 Q 连接；AAC 表示键或由 1 至 5 个二价 a-氨基酸残基组成的二价基，该二价基 N 端与基 Q 连接，C 端与基 R1 连接、R1 表示羟基、醚化羟基、氨基或取代氨基，但从 a-氨基酸衍生的氨基基除外；R2 表示氢或酰基，但天然氨基酸的任选 N-取代酰基除外；Q 表示二价基，它是二肽的异构体，也可使用它们的盐。
• CUSHMAN, MARK;OH, YOUNG-IM;COPELAND, TERRY D.;OROSZLAN, STEPHEN;SNYDER, S+, J. ORG. CHEM., 56,(1991) N3, C. 4161-4167
  作者：CUSHMAN, MARK、OH, YOUNG-IM、COPELAND, TERRY D.、OROSZLAN, STEPHEN、SNYDER, S+

  DOI：——

  日期：——
• Development of methodology for the synthesis of stereochemically pure Phe.psi.[CH2N]Pro linkages in HIV protease inhibitors
  作者：Mark Cushman、Young Im Oh、Terry D. Copeland、Stephen Oroszlan、Stuart W. Snyder

  DOI：10.1021/jo00013a017

  日期：1991.6

  One of the strategies currently being pursued for the design of potential HIV protease inhibitors involves the replacement of the cleaved amide bond in a minimum peptide substrate with an aminomethylene unit. A commonly used method for the synthesis of these compounds involves a reductive alkylation of an amine with an aldehyde in the presence of sodium cyanoborohydride under acidic conditions. Accordingly, BOC-phenylalaninal (4) was reacted with the peptide-resin ProIleSer(OBzl)OResin (5) in the presence of acetic acid and sodium cyanoborohydride. The resulting product was found to consist of a mixture of diastereomers, which may result from the fact that the proline residue, which contains a secondary amine, reacts with the aldehyde to form an enamine 9 with loss of chirality at the modified Phe residue. Subsequent reduction of the iminium ion 10 would then result in production of the observed two diastereomers. In order to circumvent this problem, BOCPheProOBzl (12b) was synthesized and the central amide bond was reduced selectively with diborane. Hydrogenolysis of the benzyl protecting group gave BOCPhe-PSI[CH2N]Pro (14a), which was coupled manually to the peptide resin IleSer(OBzl)OResin to give BOCPhe-PSI[CH2N]ProIleSer(OBzl)OResin (6). Subsequent addition of amino acid residues to 6 and cleavage from the resin gave a series of stereochemically defined potential HIV protease inhibitors as single diastereomers. The most potent of these substances was ThrLeuAsnPhe-PSI[CH2N]ProIleSer (1), which displayed an IC50 of 1.1-mu-g/mL (1.4-mu-M) when tested for inhibition of HIV-1 protease. However, the epimer of 1 having the opposite configuration at the reduced Phe residue was inactive. A minimum length of seven amino acid residues appears to be necessary for effective recognition of the inhibitor by the enzyme. Further increase in chain length did not result in greater inhibitory potency.