N^α-Boc-Val-Leu N-hydroxysuccinimide ester | 84642-33-1

• 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: N^α-Boc-Val-Leu N-hydroxysuccinimide ester
• 英文别名: Boc-Val-Leu-OSu；(2,5-dioxopyrrolidin-1-yl) (2S)-4-methyl-2-[[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]pentanoate
• CAS: 84642-33-1
• 化学式: C₂₀H₃₃N₃O₇
• 分子量: 427.498
• InChiKey: SOBQOJZFQOOYKN-BBRMVZONSA-N

物化性质

• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、二氯甲烷、DMF、DMSO、乙酸乙酯

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N^α-Boc-Val-Leu N-hydroxysuccinimide ester 在 N-甲基吗啉 、 碳酸氢钠 、 氯甲酸异丁酯 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.0h， 生成 3'-N-(Nα-Boc-Val-Leu-Nε-Fmoc-Lys)-Dox
  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：

  benzyl (tert-butoxycarbonyl)-L-valyl-L-leucinate 在 palladium on activated charcoal 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 N^α-Boc-Val-Leu N-hydroxysuccinimide 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

文献信息

• A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
  作者：Sandip V. Jadhav、Anupam Bandyopadhyay、Sushil N. Benke、Sachitanand M. Mali、Hosahudya N. Gopi

  DOI：10.1039/c0ob01226b

  日期：——

  for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals

  一种简便，高效且无外消旋的方法，使用该方法合成N保护的β-氨基醇和肽醇N-羟基琥珀酰亚胺描述了活性酯。使用这种方法，可以高产率分离出二肽，三肽和五肽醇。分析了β-氨基醇，二肽和三肽醇的晶体构象，在三肽醇晶体中观察到了明确定义的III型β角。发现该方法与Fmoc-，Boc-和其他侧链保护基相容。
• Copper(ii) mediated facile and ultra fast peptide synthesis in methanol
  作者：Sachitanand M. Mali、Sandip V. Jadhav、Hosahudya N. Gopi

  DOI：10.1039/c2cc32581k

  日期：——

  A novel, ultrafast, mild and scalable amide bond formation strategy in methanol using simple thioacids and amines is described. The mechanism suggests that the coupling reactions are initially mediated by CuSO4·5H2O and subsequently catalyzed by in situ generated copper sulfide. The pure peptides were isolated in satisfactory yields in less than 5 minutes.

  描述了一种新颖的、超快速的、温和且可扩展的氨基键形成策略，该策略在甲醇中使用简单的硫酸和胺。机制表明，偶联反应最初由硫酸铜·5水合物介导，随后由原位生成的硫化铜催化。纯肽的分离在不到5分钟的时间内获得了令人满意的产率。
• Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin
  作者：Prasun K. Chakravarty、Philip L. Carl、Michael J. Weber、John A. Katzenellenbogen

  DOI：10.1021/jm00359a004

  日期：1983.5

  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.