BOC-D-PheΨProOH | 133773-51-0

• 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: BOC-D-PheΨProOH
• 英文别名: (2S)-1-[(2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]pyrrolidine-2-carboxylic acid
• CAS: 133773-51-0
• 化学式: C₁₉H₂₈N₂O₄
• 分子量: 348.442
• InChiKey: CGIJFPZVQCRPSQ-CVEARBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  BOC-D-PheΨProOH 在 palladium on activated charcoal N-甲基吗啉 、 lithium aluminium tetrahydride 、 氢气 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 水 为溶剂， -60.0~25.0 ℃ 、101.33 kPa 条件下， 反应 28.53h， 生成 Boc-D-Phe<*>Pro-Arg-H*2HOAc
  参考文献：
  名称：

  高度选择性的三肽凝血酶抑制剂。

  摘要：

  三肽醛，例如Boc-D-Phe-Pro-Arg-H（51），表现出对凝血酶的直接有效抑制作用。这种区别为设计更有效和更具选择性的丝氨酸蛋白酶抑制剂提供了重要的见识，这些抑制剂可能是有用的药理工具，并有望开发出临床有用的药物。讨论了一系列对凝血酶具有高选择性的抗凝肽的构效关系（SAR）。SAR以51的结构为基础，以一系列的二肽和三肽精氨酸醛为中心。通过用构象受限的芳香族氨基酸，芳香族氨基酸和一种氨基酸取代，研究了位置1上氨基酸残基的结构和构象作用。包含psi [CH2N]酰胺键替代物的二肽等排物。通过比较体外对胰蛋白酶，纤溶酶，Xa因子和组织纤溶酶原激活物的抑制作用，可以确定许多这些肽具有强大的抗血栓形成活性以及对凝血酶的选择性。化合物5f，D-1-Tiq-Pro-Arg-H。硫酸盐具有很高的活性，是迄今为止报道的对凝血酶最具选择性的三肽醛抑制剂。

  DOI：

  10.1021/jm00055a002

文献信息

• 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.