[(1S,2R)-2-acetamido-1-phenylpropyl] [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]phenyl]methyl carbonate | 410093-13-9

• 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: [(1S,2R)-2-acetamido-1-phenylpropyl] [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]phenyl]methyl carbonate
• CAS: 410093-13-9
• 化学式: C₃₈H₄₈N₆O₉
• 分子量: 732.834
• InChiKey: FNKIHQRKMKGENC-JMHOIKKCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  53
• 可旋转键数：
  21
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  216
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  [(1S,2R)-2-acetamido-1-phenylpropyl] [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]phenyl]methyl carbonate 在 乙二胺四乙酸 、 acetate buffer 、 bovine spleen cathepsin B 作用下， 以 水 为溶剂， 生成 (+/-)-N-acetylnorephedrine 、 N-[(benzyloxy)carbonyl]-L-valyl-N5-carbamoyl-L-ornithine
  参考文献：
  名称：

  Protease-Mediated Fragmentation of p-Amidobenzyl Ethers:  A New Strategy for the Activation of Anticancer Prodrugs

  摘要：

  A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described. Model studies were undertaken with the N-protected peptide benzyloxycarbonyl-valine-citrulline (Z-val-cit), which was attached to the amino groups of p-aminobenzyl ether derivatives of 1-naphthol and N-acetylnorephedrine. The amide bond that formed was designed for hydrolysis by cathepsin B, a protease associated with rapidly growing and metastatic carcinomas. Upon treatment with the enzyme, the Z-val-cit p-amidobenzyl ether of 1-naphthol (2) underwent peptide bond hydrolysis with the rapid release of 1-naphthol. The aliphatic Z-val-cit p-amidobenzyl ether of N-acetylnorephedrine (5) also underwent amide bond hydrolysis, but without the ensuing elimination of N-acetylnorephedrine. On the basis of these results, the phenolic anticancer drugs etoposide (6) and combretastatin A-4 (7) were attached to the Z-val-cit p-amidobenzyl alcohol through ether linkages, forming the peptide-drug derivatives 8 and 9, respectively. Both compounds were stable in aqueous buffers and serum and underwent ether fragmentation upon treatment with cathepsin B, resulting in the release of the parent drugs in chemically unmodified forms. The released drugs were 13-50 times more potent than were the prodrug precursors on a panel of cancer cell lines. In contrast, the corresponding carbonate derivative of combretastatin A-4 (13) was unstable in aqueous environments and was as cytotoxic as combretastatin A-4. This result extends the use of the self-immolative p-aminobenzyl group for the fragmentation of aromatic ethers and provides a new strategy for anticancer prodrug development.

  DOI：

  10.1021/jo016187+
• 作为产物：
  描述：

  左旋去甲麻黄碱 在 吡啶 、 4-二甲氨基吡啶 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 27.25h， 生成 [(1S,2R)-2-acetamido-1-phenylpropyl] [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]phenyl]methyl carbonate
  参考文献：
  名称：

  Protease-Mediated Fragmentation of p-Amidobenzyl Ethers:  A New Strategy for the Activation of Anticancer Prodrugs

  摘要：

  A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described. Model studies were undertaken with the N-protected peptide benzyloxycarbonyl-valine-citrulline (Z-val-cit), which was attached to the amino groups of p-aminobenzyl ether derivatives of 1-naphthol and N-acetylnorephedrine. The amide bond that formed was designed for hydrolysis by cathepsin B, a protease associated with rapidly growing and metastatic carcinomas. Upon treatment with the enzyme, the Z-val-cit p-amidobenzyl ether of 1-naphthol (2) underwent peptide bond hydrolysis with the rapid release of 1-naphthol. The aliphatic Z-val-cit p-amidobenzyl ether of N-acetylnorephedrine (5) also underwent amide bond hydrolysis, but without the ensuing elimination of N-acetylnorephedrine. On the basis of these results, the phenolic anticancer drugs etoposide (6) and combretastatin A-4 (7) were attached to the Z-val-cit p-amidobenzyl alcohol through ether linkages, forming the peptide-drug derivatives 8 and 9, respectively. Both compounds were stable in aqueous buffers and serum and underwent ether fragmentation upon treatment with cathepsin B, resulting in the release of the parent drugs in chemically unmodified forms. The released drugs were 13-50 times more potent than were the prodrug precursors on a panel of cancer cell lines. In contrast, the corresponding carbonate derivative of combretastatin A-4 (13) was unstable in aqueous environments and was as cytotoxic as combretastatin A-4. This result extends the use of the self-immolative p-aminobenzyl group for the fragmentation of aromatic ethers and provides a new strategy for anticancer prodrug development.

  DOI：

  10.1021/jo016187+

文献信息

• Protease-Mediated Fragmentation of <i>p-</i>Amidobenzyl Ethers:  A New Strategy for the Activation of Anticancer Prodrugs
  作者：Brian E. Toki、Charles G. Cerveny、Alan F. Wahl、Peter D. Senter

  DOI：10.1021/jo016187+

  日期：2002.3.1

  A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described. Model studies were undertaken with the N-protected peptide benzyloxycarbonyl-valine-citrulline (Z-val-cit), which was attached to the amino groups of p-aminobenzyl ether derivatives of 1-naphthol and N-acetylnorephedrine. The amide bond that formed was designed for hydrolysis by cathepsin B, a protease associated with rapidly growing and metastatic carcinomas. Upon treatment with the enzyme, the Z-val-cit p-amidobenzyl ether of 1-naphthol (2) underwent peptide bond hydrolysis with the rapid release of 1-naphthol. The aliphatic Z-val-cit p-amidobenzyl ether of N-acetylnorephedrine (5) also underwent amide bond hydrolysis, but without the ensuing elimination of N-acetylnorephedrine. On the basis of these results, the phenolic anticancer drugs etoposide (6) and combretastatin A-4 (7) were attached to the Z-val-cit p-amidobenzyl alcohol through ether linkages, forming the peptide-drug derivatives 8 and 9, respectively. Both compounds were stable in aqueous buffers and serum and underwent ether fragmentation upon treatment with cathepsin B, resulting in the release of the parent drugs in chemically unmodified forms. The released drugs were 13-50 times more potent than were the prodrug precursors on a panel of cancer cell lines. In contrast, the corresponding carbonate derivative of combretastatin A-4 (13) was unstable in aqueous environments and was as cytotoxic as combretastatin A-4. This result extends the use of the self-immolative p-aminobenzyl group for the fragmentation of aromatic ethers and provides a new strategy for anticancer prodrug development.