Lys(hArg)-Pro-Dab-Arg

• 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: Lys(hArg)-Pro-Dab-Arg
• 英文别名: Lys(Har)-Pro-Dab-Arg；H-Lys(1)-Pro-Dab-Arg-OH.H-hArg-(1)；(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-amino-6-[[(2S)-2-amino-6-(diaminomethylideneamino)hexanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]butanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid
• 化学式: C₂₈H₅₅N₁₃O₆
• 分子量: 669.828
• InChiKey: KEOLKARRQWYUKW-SXYSDOLCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -8.4
• 重原子数：
  47
• 可旋转键数：
  23
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  352
• 氢给体数：
  11
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  Fmoc-Arg(Pbf)-Wang resin 、 NAlpha-BOC-Nε-FMOC-L-赖氨酸 、 Fmoc-L-脯氨酸 、 3,5-二甲基吡唑-1-硝酸咪 、 (S)-2-(Boc-氨基)-4-(Fmoc-氨基)丁酸 在 哌啶 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 Lys(hArg)-Pro-Dab-Arg
  参考文献：
  名称：

  Branched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to Neuropilin-1: Design, synthesis and biological activity

  摘要：

  The demonstrated involvement of VEGF(165)/NRP-1 complex in pathological angiogenesis has catalyzed interest in blocking this interaction to combat angiogenesis dependent diseases. It was shown before that Lys-Pro-Pro-Arg is a fairly strong inhibitor of the VEGF(165)/NRP-1 interaction. Our current findings suggest that the side chain elongation of the Lysl by branching it with additional homoarginine (Har) residue, to obtain Lys(Har)-Pro-Pro-Arg, allows more effective inhibition. Moreover, increasing the flexibility of the middle part of molecule, in particular with simultaneous introduction of additional interacting elements at the second or third position, produced compounds up to 30-fold more active (IC50 = 0.2 1.1M) than the heptapeptide ATWLPPR (A7R) which is one of the first peptide known as an effective antagonist of the VEGF(165) binding to NRP-1 and in vivo decreases breast cancer angiogenesis and growth. Herein, we present also the structure-activity study of Lys(Har)-Pro-Pro-Arg, discussing the design, synthesis, inhibitory activity, proteolytic stability and molecular modeling of the prepared derivatives. For two of the most active analogs the high proteolytic stability was also observed. These studies provide the next step for elucidating the optimal structure of the small peptidic inhibitors of VEGF(165)/NRP-1 interaction that could serve as research tools or be prospective drug candidates. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.08.083

文献信息

• Branched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to Neuropilin-1: Design, synthesis and biological activity
  作者：Dagmara Tymecka、Anna K. Puszko、Piotr F.J. Lipiński、Bartlomiej Fedorczyk、Beata Wilenska、Karolina Sura、Gerard Y. Perret、Aleksandra Misicka

  DOI：10.1016/j.ejmech.2018.08.083

  日期：2018.10

  The demonstrated involvement of VEGF(165)/NRP-1 complex in pathological angiogenesis has catalyzed interest in blocking this interaction to combat angiogenesis dependent diseases. It was shown before that Lys-Pro-Pro-Arg is a fairly strong inhibitor of the VEGF(165)/NRP-1 interaction. Our current findings suggest that the side chain elongation of the Lysl by branching it with additional homoarginine (Har) residue, to obtain Lys(Har)-Pro-Pro-Arg, allows more effective inhibition. Moreover, increasing the flexibility of the middle part of molecule, in particular with simultaneous introduction of additional interacting elements at the second or third position, produced compounds up to 30-fold more active (IC50 = 0.2 1.1M) than the heptapeptide ATWLPPR (A7R) which is one of the first peptide known as an effective antagonist of the VEGF(165) binding to NRP-1 and in vivo decreases breast cancer angiogenesis and growth. Herein, we present also the structure-activity study of Lys(Har)-Pro-Pro-Arg, discussing the design, synthesis, inhibitory activity, proteolytic stability and molecular modeling of the prepared derivatives. For two of the most active analogs the high proteolytic stability was also observed. These studies provide the next step for elucidating the optimal structure of the small peptidic inhibitors of VEGF(165)/NRP-1 interaction that could serve as research tools or be prospective drug candidates. (C) 2018 Elsevier Masson SAS. All rights reserved.