methyl (2S)-3-methyl-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]-6-[[1-[(2R,3R,4S,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]triazol-4-yl]methoxycarbonylamino]hexanoyl]amino]butanoate | 1202705-07-4

• 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: methyl (2S)-3-methyl-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]-6-[[1-[(2R,3R,4S,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]triazol-4-yl]methoxycarbonylamino]hexanoyl]amino]butanoate
• CAS: 1202705-07-4
• 化学式: C₄₄H₆₃N₇O₁₇
• 分子量: 962.021
• InChiKey: FQEDOBRAZVYCQG-OFRLVIMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  68
• 可旋转键数：
  30
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  306
• 氢给体数：
  4
• 氢受体数：
  19

反应信息

• 作为产物：
  描述：

  Boc-Phe-Lys(Poc)-Val-OMe 、 2-(乙酰氧基甲基)-6-叠氮基四氢-2H-吡喃-3,4,5-三基三乙酸酯 在 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 叔丁醇 为溶剂， 以85%的产率得到methyl (2S)-3-methyl-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]-6-[[1-[(2R,3R,4S,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]triazol-4-yl]methoxycarbonylamino]hexanoyl]amino]butanoate
  参考文献：
  名称：

  Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

  摘要：

  Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket accommodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.10.003

文献信息

• Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity
  作者：Subhra Prakash Chakrabarty、Ramesh Ramapanicker、Roli Mishra、Srinivasan Chandrasekaran、Hemalatha Balaram

  DOI：10.1016/j.bmc.2009.10.003

  日期：2009.12

  Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket accommodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range. (C) 2009 Elsevier Ltd. All rights reserved.