Nα-Fmoc-D-Val-Leu-Nε-Fmoc-Lys benzyl ester | 84624-18-0

• 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: Nα-Fmoc-D-Val-Leu-Nε-Fmoc-Lys benzyl ester
• 英文别名: N^α-Fmoc-D-Val-Leu-N^ε-Fmoc-Lys benzyl ester
• CAS: 84624-18-0
• 化学式: C₅₄H₆₀N₄O₈
• 分子量: 893.092
• InChiKey: QPRKPGXDLTUVAZ-ALKIKZFASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.02
• 重原子数：
  66.0
• 可旋转键数：
  20.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  161.16
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  Nα-Fmoc-D-Val-Leu-Nε-Fmoc-Lys benzyl ester 在 氢溴酸 作用下， 以 溶剂黄146 为溶剂， 反应 2.5h， 以95%的产率得到D-(N-9-fluorenylmethoxycarbonylvalyl)-L-leucyl-L-(Nω-9-fluorenylmethoxycarbonyl)lysine
  参考文献：
  名称：

  Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin

  摘要：

  We have synthesized peptidyl prodrugs of doxorubicin (Dox) designed to be selective substrates of plasmin. Such prodrugs might be locally activated by the elevated levels of plasmin produced near many solid tumors under the action of tumor-associated plasminogen activators. One such prodrug, 3'-(D-Val-Leu-Lys)-Dox, was obtained via a mixed-anhydride coupling with isobutyl chloroformate between the protected peptide Fmoc-D-Val-Leu-N epsilon-Fmoc-Lys-OH and doxorubicin, followed by removal of the Fmoc groups with anhydrous ammonia. Compared to doxorubicin, the prodrug showed about a 7-fold improved selective cytotoxicity against chicken embryo fibroblasts transformed with the Rous sarcoma virus (which produce high levels of plasminogen activator) compared to normal cells (which produce low levels of plasminogen activator). However, the prodrug was a very poor plasmin substrate, and although in vivo tests against the murine B16 melanoma showed that the prodrug was active, the maximum T/C obtained was less than that achieved by doxorubicin even at 25 times the molar concentration of prodrug. Qualitatively similar results were obtained for a far more hydrophobic prodrug, 3'-(Boc-Val-Leu-Lys)-Dox. These results demonstrate that peptidyl prodrugs of doxorubicin designed as plasmin substrates are more selective anticancer agents in vitro than doxorubicin itself but that the bulky anthracycline moiety probably prevents efficient plasmin-catalyzed conversion to the active parent drug, so that, in their present form, these drugs are not potent enough to allow a determination as to whether or not they are more selective in vivo.

  DOI：

  10.1021/jm00359a004
• 作为产物：
  描述：

  Fmoc-D-缬氨酸 在 N-甲基吗啉 、 氢溴酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N'-二环己基碳二亚胺 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.0h， 生成 Nα-Fmoc-D-Val-Leu-Nε-Fmoc-Lys benzyl ester
  参考文献：
  名称：

  Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin

  摘要：

  We have synthesized peptidyl prodrugs of doxorubicin (Dox) designed to be selective substrates of plasmin. Such prodrugs might be locally activated by the elevated levels of plasmin produced near many solid tumors under the action of tumor-associated plasminogen activators. One such prodrug, 3'-(D-Val-Leu-Lys)-Dox, was obtained via a mixed-anhydride coupling with isobutyl chloroformate between the protected peptide Fmoc-D-Val-Leu-N epsilon-Fmoc-Lys-OH and doxorubicin, followed by removal of the Fmoc groups with anhydrous ammonia. Compared to doxorubicin, the prodrug showed about a 7-fold improved selective cytotoxicity against chicken embryo fibroblasts transformed with the Rous sarcoma virus (which produce high levels of plasminogen activator) compared to normal cells (which produce low levels of plasminogen activator). However, the prodrug was a very poor plasmin substrate, and although in vivo tests against the murine B16 melanoma showed that the prodrug was active, the maximum T/C obtained was less than that achieved by doxorubicin even at 25 times the molar concentration of prodrug. Qualitatively similar results were obtained for a far more hydrophobic prodrug, 3'-(Boc-Val-Leu-Lys)-Dox. These results demonstrate that peptidyl prodrugs of doxorubicin designed as plasmin substrates are more selective anticancer agents in vitro than doxorubicin itself but that the bulky anthracycline moiety probably prevents efficient plasmin-catalyzed conversion to the active parent drug, so that, in their present form, these drugs are not potent enough to allow a determination as to whether or not they are more selective in vivo.

  DOI：

  10.1021/jm00359a004