7-aminoaziridinomitosene | 103422-25-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 7-aminoaziridinomitosene
• 英文别名: [(4S,6S)-11-amino-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,11-trien-8-yl]methyl carbamate
• CAS: 103422-25-9
• 化学式: C₁₄H₁₄N₄O₄
• 分子量: 302.29
• InChiKey: AVQKBCXTSUBBSU-RCOVLWMOSA-N

物化性质

• 沸点：
  663.7±55.0 °C(Predicted)
• 密度：
  2.00±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  7-aminoaziridinomitosene 生成 丝裂霉素相关化合物1
  参考文献：
  名称：

  HAN, INSOOK;KOHN, HAROLD, J. ORG. CHEM., 56,(1991) N5, C. 4648-4653

  摘要：

  DOI：
• 作为产物：
  描述：

  mitomycin C 在 1,3-丙二硫醇 、 sodium carbonate 作用下， 以 水 、 乙腈 为溶剂， 生成 7-aminoaziridinomitosene
  参考文献：
  名称：

  还原活化的丝裂霉素C与碳酸氢盐水溶液的反应：顺式-1-羟基-2,7-二氨基光油烯的恶唑烷酮衍生物的分离和表征

  摘要：

  在碳酸氢盐水溶液中丝裂霉素C的还原活化导致形成先前未知的化合物，其特征为顺式-1-羟基-2,7-二氨基油菜酮的恶唑烷酮衍生物。该化合物是碳酸氢盐与叠氮基叠氮烯的氮丙啶环的环化反应的结果，并且在接近生理血浆中存在的碳酸氢盐浓度下观察到。

  DOI：

  10.1016/j.bmcl.2009.11.046

文献信息

• Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts
  作者：Elise Champeil、Shu-Yuan Cheng、Bik Tzu Huang、Marta Conchero-Guisan、Thibaut Martinez、Manuel M. Paz、Anne-Marie Sapse

  DOI：10.1016/j.bioorg.2016.02.003

  日期：2016.4

  Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) – a derivative of MC lacking the carbamate on C10 – are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-links (ICLs). The major monoadducts generated by MC and DMC in tumor cells have opposite stereochemistry at carbon one of the guanine–mitosene bond:

  丝裂霉素C（MC）和脱氨基甲酰丝裂霉素C（DMC）是MC的衍生物，在C10上缺少氨基甲酸酯，它们是DNA烷基化剂。它们的细胞毒性归因于它们产生DNA单加合物以及链内和链间交联（ICL）的能力。MC和DMC在肿瘤细胞中产生的主要单加合物在鸟嘌呤-次油烯键的碳原子上具有相反的立体化学：MC的反式（或α）和DMC的顺式（或β）。我们假设从反式或顺式加合物的DNA结构的局部破坏是由MC和DMC产生不同的生化反应的原因。获得带有顺式和反式MC / DMC损伤的DNA底物对于验证这一假设至关重要。带有反式损伤的合成寡核苷酸可以通过仿生方法获得。但是，这种方法不会产生顺式加合物。该报告介绍了顺式次生多面体DNA加合物的首次化学合成。我们还通过分析脱氧鸟苷与MC或DMC在多种激活条件下反应中顺式和反式加合物的形成，研究了这两种药物在单核苷酸水平上表现出的立体偏好。此外，我们进行了密度泛函理论计算，以评估这
• Studies on the reactivity of reductively activated mitomycin C
  作者：Pascal Schiltz、Harold Kohn

  DOI：10.1021/ja00076a007

  日期：1993.11

  Mitomycin C (1a), a clinically significant antineoplastic antiobiotic, is considered to be the prototype of bioreductive alkylating agents. It has been reported that, in the absence of DNA, reductive activation of 1a furnished both solvolytic C(1) electrophilic (2,7-diaminomitosene (7)) and C(1) nucleophilic (trans-(8) and cis-1-hydroxy-diaminomitosene (9)) products. The detection of 7 as well as 8

  丝裂霉素 C (1a) 是一种具有临床意义的抗肿瘤抗生素，被认为是生物还原性烷化剂的原型。据报道，在没有 DNA 的情况下，1a 的还原活化提供了溶剂溶解的 C(1) 亲电（2,7-二氨基线粒体 (7)）和 C(1) 亲核（反式（8）和顺式 1 -羟基-二氨基二甲苯 (9)) 产品。7 以及 8 和 9 的检测表明，氮丙啶开环醌甲基化物 4 是两组产物的前体。在几乎完全消耗 1a 的条件下，连二亚硫酸钠介导的丝裂霉素 C 还原表明，在 pH 5.5 和 8.5 之间，质子捕获得到 7 是主要过程（77.2-87.8%）
• Preparation and antitumor activity of 7-substituted 1,2-aziridinomitosenes
  作者：Bhashyam S. Iyengar、William A. Remers、William T. Bradner

  DOI：10.1021/jm00160a012

  日期：1986.10

  7-Methoxy-1,2-aziridinomitosenes were prepared from mitomycin A and its N-methyl homologue by catalytic reduction followed by air oxidation. Treatment of these products with amines, including ammonia, ethylenimine, 2-methylethylenimine, propargylamine, and furfurylamine gave the corresponding 7-(substituted amino) derivatives. Screening of these compounds against P-388 leukemia in mice revealed some good activities. The more easily reduced compounds gave prolongation of life span comparable to that of mitomycin C, but their optimal doses were higher. Among these compounds, a methyl group on the aziridine nitrogen increased potency. The 7-amino derivatives, which were difficult to reduce to hydroquinones, were essentially inactive. The aziridinomitosenes were subjected to a Hansch-type analysis, but no statistically significant correlation was found.
• Studies on the mechanism of mitomycin C(1) electrophilic transformations: structure-reactivity relationships
  作者：Insook Han、David J. Russell、Harold Kohn

  DOI：10.1021/jo00032a037

  日期：1992.3

  Previous studies have demonstrated that reductive activation of mitomycin C (1) under acidic conditions furnished high yields of the C(1) electrophilic product 2,7-diaminomitosene (5). This adduct was also the major metabolite produced upon administration of 1 to HT-29 cytosol, purified HT-29 colon carcinoma cells, and rat hepatic DT-diaphorase. Proton capture at C(1) in 1 is known to proceed with high stereoselectivity. Information concerning the mechanism and the controlling factors that govern this transformation have been determined by examining the structure-reactivity relationship for mitomycin C (1), 10-decarbamoylmitomycin C (10), N(1a)-methyl-10-decarbamoyl-10-acetoxymitomycin C (11), mitomycin D (12), 10-decarbamoylmitomycin D (13), 7-aminoaziridinomitosene (14), N(1a)-(methanesulfonyl)mitomycin C (15), and N(1a)-(toluenesulfonyl)mitomycin C (16). The combined results obtained were consistent with the hypothesis that mitomycin C C(1) electrophilic reactions funneled through quinone methide 4. The high stereoselectivity of this process has been attributed (in part) to the protonated C(2) amino group in 4. In this scenario, proton capture occurred preferentially from the site opposite to the C(2) ammonium group in order to minimize adverse coulombic interactions.
• 7-Aminoaziridinomitosenes: synthesis, structure, and chemistry
  作者：Insook Han、Harold Kohn

  DOI：10.1021/jo00015a016

  日期：1991.7

  7-Aminoleucoaziridinomitosene (2a) has been proposed as a key intermediate in the reductive activation process for the antineoplastic agent, mitomycin C (1a). Little is known about 2a and its oxidized equivalent, 7-aminoaziridinomitosene (3a). An expedient electrochemical procedure for 3a and the corresponding N-methyl analogue 3b has been developed. NMR spectral studies of 3a in DMF-d7 and DMSO-d6 provided important information concerning the solution-state structure for this adduct. Factors controlling the aziridine ring-opening process under reductive and nonreductive conditions have been determined, as well as evidence for the intermediacy of 2a in the reductive activation cascade of 1a.