Cbz-D-Val-Leu-N⁶-Cbz-Lys-OH | 88246-14-4

• 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: Cbz-D-Val-Leu-N⁶-Cbz-Lys-OH
• 英文别名: Z-D-Val-L-Leu-L-Lys(Z)-OH；Z-D-Val-Leu-Lys(Z)-OH；Cbz-D-Val-Leu-Lys(Cbz)(Cbz)-OH；(2S)-2-[[(2S)-4-methyl-2-[[(2R)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoyl]amino]-6-(phenylmethoxycarbonylamino)hexanoic acid
• CAS: 88246-14-4
• 化学式: C₃₃H₄₆N₄O₈
• 分子量: 626.75
• InChiKey: GUYPNCICNNNKGP-HZFUHODCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  45
• 可旋转键数：
  20
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  172
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Cbz-D-Val-Leu-N⁶-Cbz-Lys-OH 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 Z-D-Val-Leu-Lys(Z)-N(Me)-(CH2)2-N(Me)-Boc
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 2‘-Carbamate-Linked and 2‘-Carbonate-Linked Prodrugs of Paclitaxel:  Selective Activation by the Tumor-Associated Protease Plasmin

  摘要：

  The nontoxic paclitaxel-2'-carbamate prodrugs 2-5 and paclitaxel-2'-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paditaxel-2'-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3-6 were highly stable. Prodrugs 3-6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.

  DOI：

  10.1021/jm0009078
• 作为产物：
  描述：

  N-苄氧羰基-D-缬氨酸 在 N-甲基吗啉 、 sodium hydroxide 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 吡啶 、 水 为溶剂， 反应 80.0h， 生成 Cbz-D-Val-Leu-N⁶-Cbz-Lys-OH
  参考文献：
  名称：

  Synthesis and functional evaluation of a peptide derivative of 1-.beta.-D-arabinofuranosylcytosine

  摘要：

  We have synthesized a peptidyl prodrug derivative of 1-beta-D-arabinofuranosylcytosine (1) designed to be a selective substrate of plasmin. D-Val-Leu-Lys-ara-C (2) was obtained by coupling the protected peptide Cbz-D-Val-Leu-(N6-Cbz)Lys-OH and ara-C (1) by a water-soluble carbodiimide (EDCI), followed by the removal of the Cbz groups by using catalytic hydrogenolysis over Pd/C. The kinetic constant of hydrolysis of 2 in the presence of plasmin demonstrated effective release of 1. The amino group of 1, which is sensitive to the removal by cytidine deaminase, is protected in 2 by the formation of the amide bond resulting in a prolonged half-life of 2 in biological milieu. The antiproliferative efficiency of 2 against L1210 leukemic cells was significantly higher than that of 1. The activity of 2 was abolished in the presence of serine proteinase inhibitor, (4-amidinopheny)methanesulfonyl fluoride. These data indicate that 2 is a prodrug form of 1 in systems generating plasmin.

  DOI：

  10.1021/jm00096a006

文献信息

• AKIYAMA, SINITI;TAXARA, IOSIYUKI;TAKAXASI, TOSIXIRO;MAEHDA, YUKITSERU
  作者：AKIYAMA, SINITI、TAXARA, IOSIYUKI、TAKAXASI, TOSIXIRO、MAEHDA, YUKITSERU

  DOI：——

  日期：——
• Midura-Nowaczek; Bruzgo; Roszkowska-Jakimiec, Revista Bras il eira de Farmaco gnosia, 1997, vol. 52, # 1, p. 35 - 37
  作者：Midura-Nowaczek、Bruzgo、Roszkowska-Jakimiec、Worowski

  DOI：——

  日期：——
• Synthesis and functional evaluation of a peptide derivative of 1-.beta.-D-arabinofuranosylcytosine
  作者：Zoltan Balajthy、Janos Aradi、Ildiko T. Kiss、Pal Elodi

  DOI：10.1021/jm00096a006

  日期：1992.9

  We have synthesized a peptidyl prodrug derivative of 1-beta-D-arabinofuranosylcytosine (1) designed to be a selective substrate of plasmin. D-Val-Leu-Lys-ara-C (2) was obtained by coupling the protected peptide Cbz-D-Val-Leu-(N6-Cbz)Lys-OH and ara-C (1) by a water-soluble carbodiimide (EDCI), followed by the removal of the Cbz groups by using catalytic hydrogenolysis over Pd/C. The kinetic constant of hydrolysis of 2 in the presence of plasmin demonstrated effective release of 1. The amino group of 1, which is sensitive to the removal by cytidine deaminase, is protected in 2 by the formation of the amide bond resulting in a prolonged half-life of 2 in biological milieu. The antiproliferative efficiency of 2 against L1210 leukemic cells was significantly higher than that of 1. The activity of 2 was abolished in the presence of serine proteinase inhibitor, (4-amidinopheny)methanesulfonyl fluoride. These data indicate that 2 is a prodrug form of 1 in systems generating plasmin.
• Synthesis and Biological Evaluation of 2‘-Carbamate-Linked and 2‘-Carbonate-Linked Prodrugs of Paclitaxel:  Selective Activation by the Tumor-Associated Protease Plasmin
  作者：Franciscus M. H. de Groot、Leon W. A. van Berkom、Hans W. Scheeren

  DOI：10.1021/jm0009078

  日期：2000.8.1

  The nontoxic paclitaxel-2'-carbamate prodrugs 2-5 and paclitaxel-2'-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paditaxel-2'-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3-6 were highly stable. Prodrugs 3-6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.