N-(9-fluorenylmethoxycarbonyl)-p-(N-cyclohexylmethyl-N'-tert-butyloxycarbonylamino)-L-phenylalanine | 1443132-15-7

• 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: N-(9-fluorenylmethoxycarbonyl)-p-(N-cyclohexylmethyl-N'-tert-butyloxycarbonylamino)-L-phenylalanine
• 英文别名: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((tert-butoxycarbonyl)(cyclohexylmethyl)amino)phenyl)propanoic acid；Fmoc-(S)-2-amino-3-(4-(tertbutoxycarbonyl(cyclohexylmethyl)amino)phenyl)propanoic acid；(2S)-3-[4-[tert-butoxycarbonyl(cyclohexylmethyl)amino]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid；(2S)-3-[4-[cyclohexylmethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
• CAS: 1443132-15-7
• 化学式: C₃₆H₄₂N₂O₆
• 分子量: 598.739
• InChiKey: JCFXPKHKPYVDBV-YTTGMZPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  44
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(9-fluorenylmethoxycarbonyl)-p-(N-cyclohexylmethyl-N'-tert-butyloxycarbonylamino)-L-phenylalanine 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2S)-3-[4-[cyclohexylmethyl(pent-4-enoyl)amino]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
  参考文献：
  名称：

  Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor

  摘要：

  One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.006
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 N-(9-fluorenylmethoxycarbonyl)-p-(N-cyclohexylmethylamino)-L-phenylalanine 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 72.0h， 以94.8%的产率得到N-(9-fluorenylmethoxycarbonyl)-p-(N-cyclohexylmethyl-N'-tert-butyloxycarbonylamino)-L-phenylalanine
  参考文献：
  名称：

  Interfacial Cavity Filling To Optimize CD4–Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein

  摘要：

  Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 nonnatural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure. with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity.

  DOI：

  10.1021/jm4002988