6-(1-aziridinyl)-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole-5,8-dione | 150747-50-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-(1-aziridinyl)-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole-5,8-dione
• 英文别名: 6-Aziridin-1-yl-3-hydroxy-7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5,8-dione；6-(aziridin-1-yl)-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
• CAS: 150747-50-5
• 化学式: C₁₃H₁₃N₃O₃
• 分子量: 259.265
• InChiKey: CUWRQGLHMSVVKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(1-aziridinyl)-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole-5,8-dione 在 重铬酸吡啶 作用下， 反应 15.0h， 以23%的产率得到6-aziridinyl-2,3-dihydro-7-methyl-(1H)-pyrrolo[1,2-a]benzimidazole-3,5,8-trione
  参考文献：
  名称：

  基于叠氮基环戊[b]吲哚醌的癌症特异性抗肿瘤药的设计。

  摘要：

  描述了N-未取代的吲哚和环戊[b]吲哚作为DNA定向的还原烷基化剂的优点。这些系统代表了与N-取代的和吡咯并[1，2-a]融合的系统（如丝裂霉素和丝裂霉素）的背离。当带有带有或不带有N-乙酰基的乙酸盐离去基团时，基于环戊[b]吲哚的叠氮基醌系统具有细胞毒性，并且对同基因肿瘤植入物显示出显着的体内活性。这些类似物在激活酶DT-黄递酶的高特异性和高DNA烷基化率方面均优于其他类似物。醌甲基化物中间体以及叠氮基烷基的烷基化可导致交联。制备了最活跃的吲哚物种可能的代谢物，发现保留了细胞毒性，提示体内活性可以持续。本研究中的吲哚系统显示出对黑色素瘤的选择性，并根据存在的取代基显示出对非小细胞肺癌，结肠癌，肾癌和前列腺癌的选择性。据信观察到的癌症特异性与DT-黄递酶的不同底物特异性有关。

  DOI：

  10.1021/jm990466w
• 作为产物：
  描述：

  在 potassium dihydrogenphosphate 、 potassium nitrososulfonate 作用下， 以 甲醇 为溶剂， 反应 20.0h， 生成 6-(1-aziridinyl)-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole-5,8-dione
  参考文献：
  名称：

  Pyrrolo[1,2-a]benzimidazole-Based Quinones and Iminoquinones. The Role of the 3-Substituent on Cytotoxicity

  摘要：

  The influence of the 3-substituent on the cytotoxicity of the 6-aziridinylpyrrolo[1,2-a]benzimidazole quinones (PBIs), the 6-acetamidopyrrolo[1,2-a]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2-a]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC(50) mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the S-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC(50) VS log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated by this enzyme. Thus the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR.

  DOI：

  10.1021/jm00001a016

文献信息

• Cytotoxic N-unsubstituted indoles and cyclopent(b)indoles and method of making and using same
  申请人：——

  公开号：US20040006054A1

  公开（公告）日：2004-01-08

  The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA-directed reductive alkylating agents are described. These systems represent a significant departure from N-substituted and pyrrolo[1,2-a] fused systems such as the mitomycins and mitosenes. The cyclopent[b]indole—based aziridinylquinone, when bearing an acetate leaving group, was found to be cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. This particular analogue was unexpectedly superior to the others studied, both in terms of high specificity for the activating enzyme DT-diaphorase and in high % DNA alkylation. Alkylation by a quinone methide intermediate as well as by the aziridinyl group were examined for crosslinking. The possible metabolites of the most active indole species were prepared and found to retain cytotoxicity, strongly suggesting that in vivo activity could also be sustained. The indole systems in the present invention display selectivity for melanoma and for non small cell lung, colon, renal, and prostate cancers when administered in an effective amount. The cancer specificity observed is believed to pertain to differential substrate specificity for DT-diaphorase.

  描述了N-未取代吲哚和环戊[b]吲哚作为DNA定向还原烷基化剂的优点。这些体系与N-取代和吡咯[1,2-a]融合体系（如丝菌素和丝菌烯）有显著不同。基于环戊[b]吲哚的氮杂环喹喙醌，当带有乙酸离去基团时，被发现具有细胞毒性，并对同基因肿瘤移植物显示出显著的体内活性。这种特定的类似物在高度特异性激活酶DT-二氧还酶和高DNA烷基化百分比方面意外地优于其他研究过的类似物。通过醌亚甲基中间体和环氧丙基基团进行了交联的烷基化研究。最活跃的吲哚物种的可能代谢产物已经制备并发现保留了细胞毒性，强烈暗示体内活性也可能持续存在。本发明中的吲哚体系在有效剂量下对黑色素瘤和非小细胞肺癌、结肠癌、肾癌和前列腺癌显示出选择性。观察到的癌症特异性被认为与DT-二氧还酶的不同底物特异性有关。
• Pyrrolo[1,2-a]benzimidazole-based aziridinyl quinones. A new class of DNA cleaving agent exhibiting G and A base specificity
  作者：Edward B. Skibo、William G. Schulz

  DOI：10.1021/jm00073a002

  日期：1993.10

  Pyrrolo[1,2-a]benzimiazole(PBI)-based aziridinyl quinones cleave DNA under reducing conditions specifically at G + A bases without any significant cleavage at C + T bases. The postulated mechanisms involve phosphate alkylation by the reductively activated aziridine to afford a hydrolytically labile phosphotriester as well as the classic N(7) purine alkylation followed by depurination and backbone cleavage. Evidence is presented that the phosphate alkylation mechanism could contribute. The PBIs possess a unique spectrum of cytotoxicity against cancer cells (inactive against leukemia but active against nonsmall cell lung, colon, CNS, melanoma, ovarian, and renal cancers). Also reported are results of in vivo antitumor activity screens.