Nα-(tert-buthoxycarbonyl)-D-valylleucyl-Nε-(tert-buthoxycarbonyl)lysine | 74202-00-9

• 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: Nα-(tert-buthoxycarbonyl)-D-valylleucyl-Nε-(tert-buthoxycarbonyl)lysine
• 英文别名: N^α-(tert-buthoxycarbonyl)-D-valylleucyl-N^ε-(tert-buthoxycarbonyl)lysine；D-(N-tert-butoxycarbonylvalyl)-L-leucyl-L-(N^ω-tert-butoxycarbonyl)lysine；[(N-tert-butoxycarbonyl-D-valyl)-L-leucyl]-N-ε-tert-butoxycarbonyl-L-lysine
• CAS: 74202-00-9
• 化学式: C₂₇H₅₀N₄O₈
• 分子量: 558.716
• InChiKey: KVIPWZHALHIDCH-SLFFLAALSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.33
• 重原子数：
  39.0
• 可旋转键数：
  14.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  172.16
• 氢给体数：
  5.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  Nα-(tert-buthoxycarbonyl)-D-valylleucyl-Nε-(tert-buthoxycarbonyl)lysine 在 N-甲基吗啉 、 氯甲酸异丁酯 作用下， 以 二氯甲烷 为溶剂， 反应 2.75h， 生成 N-(D-valylleucyllysyl)-N',N'-bis(2-chloroethyl)-p-phenylenediamine bis(trifluoroacetate)
  参考文献：
  名称：

  Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard

  摘要：

  Many tumors contain elevated levels of plasminogen activator and thus produce elevated levels of the protease plasmin in the milieu of the tumor. We have hypothesized, therefore, that it should be possible to prepare peptidyl prodrug derivatives of anticancer drugs that would be locally activated by tumor-associated plasmin. As an initial test of this hypothesis, we synthesized the peptidyl prodrugs of the anticancer drugs (alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin, AT-125) and N,N-bis(2-chloroethyl)-p-phenylenediamine (phenylenediamine mustard) by mixed anhydride coupling of the parent drug with the protected tripeptide, Boc-D-Val-Leu-Lys(Boc)-OH, followed by deprotection with trifluoroacetic acid. The prodrugs showed an increased selective in vitro cytotoxicity for Rous sarcoma virus transformed chicken embryo fibroblasts (which produce elevated levels of plasminogen activator) compared to nontransformed fibroblasts (which produce low levels of plasminogen activator). In the presence of the plasmin inhibitor, p-nitrophenyl p'-guanidinobenzoate at 2 micrograms/mL, the selectivity of the phenylenediamine mustard prodrug was reduced, but there was no effect on the cytotoxicity of the free drug. Furthermore, the prodrug analogue D-valylleucyl-D-lysylphenylenediamine mustard (in which L-Lys has been replaced by D-Lys) was inactive. Finally, the prodrug derivative of acivicin did not display selective toxicity for transformed cells when the cells were cultured in plasminogen-free medium. These results suggest that plasmin hydrolysis is necessary for the activation of the prodrugs. The prodrugs were tested in vivo for antitumor activity. The prodrug of acivicin, like acivicin itself, was inactive against the B16 melanoma, a murine tumor that produces high levels of plasminogen activator. This prodrug was active against the M5076 carcinoma, a tumor that displays only moderate levels of plasminogen activator; however, despite the fact that the prodrug was 2- to 3-fold less toxic on a molar basis than acivicin, there was no evidence of an increased therapeutic index. The prodrug of phenylenediamine mustard was also slightly less toxic than the parent drug, but again there was no evidence for an improved therapeutic index against the B16 tumor.

  DOI：

  10.1021/jm00359a003
• 作为产物：
  描述：

  L-亮氨酸甲酯盐酸盐 在 N-甲基吗啉 、 sodium hydroxide 、 N-羟基丁二酰亚胺 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 50.0h， 生成 Nα-(tert-buthoxycarbonyl)-D-valylleucyl-Nε-(tert-buthoxycarbonyl)lysine
  参考文献：
  名称：

  An Approach Towards More Selective Anticancer Agents

  摘要：

  一种有前景的方法是利用与人类恶性肿瘤相关的蛋白酶增强表达来更好地靶向抗癌药物治疗。特别是，已经发现纤溶酶原激活剂的活性显著提高，导致丝氨酸蛋白酶纤溶酶的活性增加。双功能烷基化剂，如N-(2-氯乙基)-N-亚硝基脲，显示出广泛的抗癌活性，但也表现出相当大的全身毒性。我们在这里描述了一种新型N-亚硝基脲类前药的合成，这些前药设计为通过肿瘤相关的蛋白酶激活，以提供增强的抗肿瘤活性和减少的全身毒性。代表纤溶酶底物的三肽通过酰胺键连接到N’-(2-氨基乙基)-N-(2-氯乙基)-N-亚硝基脲及相应的N’-甲基衍生物。我们描述了这些新三肽结合物的合成和纤溶酶触发的分解。表达高纤溶酶原激活剂活性的癌细胞在纤溶酶原存在的情况下对新前药高度敏感，但在缺乏的情况下则不然。

  DOI：

  10.1055/s-1996-4368

文献信息

• Intramolecular Opening of β-Lactams with Amines as a Strategy Toward Enzymatically or Photochemically Triggered Activation of Lactenediyne Prodrugs
  作者：Luca Banfi、Giuseppe Guanti、Marcello Rasparini

  DOI：10.1002/ejoc.200390188

  日期：2003.3

  to develop a general strategy for selective activation of designed enediyne prodrugs belonging to the “lactenediyne” family, we studied the scope of intramolecular transamidation of simple monocyclic β-lactams bearing a tethered amine. The effect of substituents, of reaction media, and of the type of tether, on the rate of transamidation is disclosed. The possibility of triggering the transamidation

  为了开发选择性激活属于“lactenediyne”家族的设计的烯二炔前药的一般策略，我们研究了带有束缚胺的简单单环 β-内酰胺的分子内转酰胺化的范围。公开了取代基、反应介质和系链类型对转酰胺化速率的影响。在模型单环 β-内酰胺上证明了在温和条件下通过合适的酶或紫外线的作用触发转酰胺事件的可能性。最后，β-内酰胺分子内打开导致更大的七元环的策略被用于乳糖二炔，证明环扩大可以释放烯二炔部分的反应性。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)