H-AVPPhgY-NH2 | 1372805-46-3

• 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: H-AVPPhgY-NH2
• 英文别名: AVPPhgY-NH2；H-Ala-Val-Pro-Phg-Tyr-NH(2)；(2S)-N-[(1S)-2-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-2-oxo-1-phenylethyl]-1-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carboxamide
• CAS: 1372805-46-3
• 化学式: C₃₀H₄₀N₆O₆
• 分子量: 580.684
• InChiKey: AHRUXJSHORHSLD-WCJQXVFBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  197
• 氢给体数：
  6
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  Fmoc-L-缬氨酸 、 Fmoc-L-丙氨酸 、 Fmoc-L-脯氨酸 、 Fmoc-O-叔丁基-L-酪氨酸 、 Fmoc-L-苯基甘氨酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 H-AVPPhgY-NH2
  参考文献：
  名称：

  Solid phase synthesis of Smac/DIABLO-derived peptides using a ‘Safety-Catch’ resin: Identification of potent XIAP BIR3 antagonists

  摘要：

  The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500 nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1 mu M concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.055

文献信息

• Racemisation of <i>N</i> -Fmoc phenylglycine under mild microwave-SPPS and conventional stepwise SPPS conditions: attempts to develop strategies for overcoming this
  作者：Mohamed A. Elsawy、Chandralal Hewage、Brian Walker

  DOI：10.1002/psc.2398

  日期：2012.5

  racemisation of the Phg residue and to determine at which part of the synthetic cycle the epimerization had occurred. We determined that racemisation occurred mainly during the Fmoc‐group removal and, to a much lesser extent, during activation/coupling of the Fmoc‐Phg‐OH residue. We were able to obtain the desired peptide with a 71% diastereomeric purity (29% LLLDL as impurity) by utilizing microwave‐assisted

  我们一直从事含苯甘氨酸（Phg）的五肽H‐Ala‐Val‐Pro‐Phg‐Tyr‐NH 2的微波固相肽合成（SPPS）合成工作（1）先前已证明与抗凋亡蛋白XIAP的所谓BIR3结构域结合。通过结合RP-HPLC，ESI-MS和NMR对目标肽进行分析，发现存在两种非对映异构体，这是由于Phg残基的外消旋化引起的，LLLDL组分的百分含量估计为49％。我们尝试使用不同的微波和常规逐步SPPS条件进行肽（1）的合成，以尝试降低Phg残基的外消旋化水平并确定差向异构化发生在合成周期的哪一部分。我们确定外消旋作用主要发生在Fmoc-基团的去除过程中，而在较小的程度上发生在Fmoc-Phg-OH残基的激活/偶联过程中。4与NMM作为活化剂碱一起用于该残基的掺入和20％哌啶作为Fmoc-脱保护碱的掺入。相反，上述肽的苯丙氨酸类似物H-Ala-Val-Pro-Phe-Tyr-NH 2（2）始终通过使用一系
• Solid phase synthesis of Smac/DIABLO-derived peptides using a ‘Safety-Catch’ resin: Identification of potent XIAP BIR3 antagonists
  作者：Mohamed A. Elsawy、Lorraine Martin、Irina G. Tikhonova、Brian Walker

  DOI：10.1016/j.bmc.2013.06.055

  日期：2013.9

  The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500 nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1 mu M concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines. (C) 2013 Elsevier Ltd. All rights reserved.