1-(4-carbamoylphenyl)-3-methyltriazene | 59708-26-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(4-carbamoylphenyl)-3-methyltriazene
• 英文别名: 4-(2-methyliminohydrazinyl)benzamide
• CAS: 59708-26-8
• 化学式: C₈H₁₀N₄O
• 分子量: 178.194
• InChiKey: OCUUHWNHDIMWCD-UHFFFAOYSA-N

物化性质

• 沸点：
  340.8±44.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  79.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(4-carbamoylphenyl)-3-methyltriazene 在 吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 72.0h， 生成 ditert-butyl (2S)-2-[[[(4-carbamoylphenyl)diazenyl]-methylcarbamoyl]amino]pentanedioate
  参考文献：
  名称：

  Development of triazene prodrugs for ADEPT strategy: New insights into drug delivery system based on carboxypeptidase G2 activation

  摘要：

  Six novel urea triazene prodrugs have been synthesized to apply in antibody-directed enzyme prodrug therapy (ADEPT). The chemical and plasmatic stability of L-glutamate triazene prodrugs were evaluated and the chemical reactivity was mainly attributed to an intramolecular catalysis promoted by the neighbouring carboxylate group of the glutamic moiety. These prodrugs showed an elevated binding to plasma proteins. The L-glutamate triazenes were evaluated as prodrugs of the alkylating agent's monomethyltriazenes, by activation of the bacterial enzyme carboxypeptidase G2 (CPG2). The synthesized prodrugs have been shown to be good substrates for CPG2, and therefore new candidates for ADEPT strategy. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.029
• 作为产物：
  描述：

  对氨基苯甲酰胺 在 盐酸 、 水 、 sodium nitrite 作用下， 以 水 为溶剂， 生成 1-(4-carbamoylphenyl)-3-methyltriazene
  参考文献：
  名称：

  新三氮烯化合物对人黑素瘤细胞的选择性细胞毒性

  摘要：

  转移性黑色素瘤仍然是最难克服的癌症之一。我们研究的目的是设计用于黑素瘤特异性疗法的抗肿瘤三氮烯化合物3。该策略利用了黑色素生物合成的独特酶途径，将无毒前药转化为黑素瘤细胞中的有毒药物。通过偶联两个活性部分，烷基化三氮烯和不同的酪氨酸酶底物来设计化合物3。所有化合物3在生理pH（t½≥48  h）时在等渗磷酸盐缓冲液（PBS）中化学稳定，并且大多数化合物在人血浆中缓慢水解（1.5≤t½（h）≤161）。化合物3c –n显示出优异的酪氨酸酶底物（0.74≤t1 /2（min）≤6），最佳酪氨酸酶底物3l在酪氨酸酶活化后释放MMT 45s。结构-活性关系研究允许鉴定更好的酶亲和力结构特征。此外，衍生物3l和3m对具有酪氨酸酶过表达MNT-1和B16F10的黑色素瘤细胞系具有明显的细胞毒性作用（IC 50值为46–65μM）。

  DOI：

  10.1016/j.bmc.2017.04.049

文献信息

• Influence of Serum Albumins on Decomposition Rates of Para- Substituted 1-phenyl-3-methyltriazenes and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide in Near Physiological Conditions
  作者：Franco Delben、Sergio Paoletti、Giorgio Manzini、Carlo Nisi

  DOI：10.1002/jps.2600700815

  日期：1981.8

  The influence of human serum albumin on the decomposition rates of some arylmonomethyltriazenes in buffered aqueous solution was investigated. From the experimental data, a model for the triazene-albumin interaction was derived, and the thermodynamic parameters were systematically calculated by two independent methods. The results show marked dependence of the energetics of binding on the substituent

  研究了人血清白蛋白对某些芳基单甲基三氮烯在缓冲水溶液中分解速率的影响。从实验数据中，得出了三氮烯-白蛋白相互作用的模型，并通过两种独立的方法系统地计算了热力学参数。结果表明，结合的能量对三氮烯芳族环中的取代基有明显的依赖性。对于大多数研究的三氮烯，与白蛋白的结合主要是焓驱动的。还使用牛和鼠血清白蛋白进行测量。
• Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability
  作者：Cláudia Braga、Ana R. Vaz、M. Conceição Oliveira、M. Matilde Marques、Rui Moreira、Dora Brites、Maria J. Perry

  DOI：10.1016/j.ejmech.2019.03.048

  日期：2019.6

  Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties than temozolomide and endowed with chemical and plasma stability. In contrast to temozolomide

  本文中，我们报告了基于丙戊酸和DNA-烷基化三氮烯部分1的新型杂合化合物，具有治疗成胶质细胞瘤多形式化学疗法的潜力。我们确定杂合化合物1d和1e与替莫唑胺相比，对神经胶质瘤的效力显着增强，并且在降低侵袭性细胞特性方面更有效，并且具有化学和血浆稳定性。与替莫唑胺发生水解以释放出烷基化代谢产物相反，丙戊酸酯杂化物显示出低的烷基化DNA潜力。关键的理化特性与CNS的最佳渗透率相吻合，突显了这些有效的基于三氮烯的杂化物在增强抗癌化学疗法方面的潜力。
• Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes
  作者：Maria de Jesus Perry、Emília Carvalho、Eduarda Rosa、Jim Iley

  DOI：10.1016/j.ejmech.2008.06.022

  日期：2009.3

  A series of 3-[α-(acylamino)acyl]-1-aryl-3-methyltriazenes 6a–l, potential cytotoxic triazene prodrugs, were synthesised by coupling 1-aryl-3-methyltriazenes to N-acylamino acids. Their hydrolysis was studied in isotonic pH 7.4 phosphate buffer and in human plasma, while hydrolysis of the derivative 6a was studied in more depth across a range of pH values. Prodrugs 6a–l hydrolyse by cleavage of the

  通过将1-芳基-3-甲基三氮烯与N-酰基氨基酸偶联，合成了一系列3- [α-（酰基氨基）酰基] -1-芳基-3-甲基三氮烯6a - 1，潜在的细胞毒性三氮烯前药。在等渗pH 7.4磷酸盐缓冲液和人血浆中研究了它们的水解，而在一系列pH值范围内更深入地研究了衍生物6a的水解。前药6a – l通过裂解三氮烯酰基水解得到相应的单甲基三氮烯。在人体血浆中的研究表明，氨基酸载体的α-氨基的酰化是降低α-氨基酰基衍生物的化学反应性同时保持快速酶水解速率的有效手段。这些衍生物显示出log  P值，表明它们应该被生物膜很好地吸收。
• Synthesis and evaluation of N-acylamino acids derivatives of triazenes. Activation by tyrosinase in human melanoma cell lines
  作者：Ana Sofia Monteiro、Joana Almeida、Guadalupe Cabral、Paulo Severino、Paula A. Videira、Ana Sousa、Rafael Nunes、João D. Pereira、Ana Paula Francisco、M. Jesus Perry、Eduarda Mendes

  DOI：10.1016/j.ejmech.2013.09.040

  日期：2013.12

  In this research work we report the synthesis of a new series of triazene prodrugs designed for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT). These compounds are derived from the N-acyltyrosine amino acid a good enzyme substrate for the tyrosinase enzyme, which is significantly overexpressed in melanoma cells. We analysed their chemical stability and plasma enzymatic hydrolysis, and we also evaluated the release of the antitumoral drug in the presence of the tyrosinase. Subsequently, we performed the evaluation of the prodrug cytotoxicity in melanoma cell lines with different levels of tyrosinase activity. Prodrug 5c showed the highest cytotoxicity against melanoma cell lines, and this effect correlated well with the tyrosinase activity suggesting that prodrug cytotoxicity is tyrosinase-dependent. (C) 2013 Elsevier Masson SAS. All rights reserved.
• ——
  作者：Emilia Carvalho、Jim Iley、Maria de Jesus Perry、Eduarda Rosa

  DOI：10.1023/a:1011988918476

  日期：——

  Purpose. The synthesis of chemically stable triazene prodrugs capable of hydrolysing under physiological conditions to liberate cytotoxic monomethyltriazene alkylating agents.Methods, A series of 3-aminoacyl-1-aryl-3-methyltriazenes was synthesised through reaction of 1-aryl-3-methyltriazenes with N-BOC protected amino acids using the DCC method of activation, followed by deprotection of the amino function using HCl in nitromethane. Half-lives for the hydrolysis of these compounds to the corresponding mono-methyltriazenes at 37 degrees C in isotonic phosphate buffer and in 80% human plasma containing 20% phosphate buffer were determined by HPLC.Results, The aminoacyltriazene prodrugs hydrolyse in isotonic phosphate buffer with tin values ranging from 26 to 619 minutes. In human plasma, several decompose at the same rate as in phosphate buffer whereas those containing more lipophilic groups decompose more slowly. A P-alanyl derivative was found to be more stable in phosphate buffer (t(1/2) = 180 minutes) than in plasma (t(1/2) = 53 minutes). An N-acetylated cr-alanyl derivative was found to be chemically stable in phosphate buffer (t(1/2) = 10 hours) but liberated the cytotoxic drug in t(1/2) = 41 minutes in plasma, demonstrating its ability to act as a substrate for plasma enzymes.Conclusions, Aminoacyltriazenes are prodrugs of the antitumour monomethyltriazenes hydrolysing in human plasma with a range of reactivities. The acylation of the alpha-amino group seems to be an effective and simple means of reducing the chemical reactivity of the alpha-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis.