N-{3-[{3-[(1,4-dioxido-1,2,4-benzotriazin-3-yl)amino]propyl}(methyl)amino]propyl}-2-(4-pyridyl)-8-quinolinecarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-{3-[{3-[(1,4-dioxido-1,2,4-benzotriazin-3-yl)amino]propyl}(methyl)amino]propyl}-2-(4-pyridyl)-8-quinolinecarboxamide
• 英文别名: n-{3-[{3-[(1,4-Dioxido-1,2,4-benzotriazin-3-yl)amino]propyl}(methyl)amino]-propyl}-2-(4-pyridyl)-8-quinolinecarboxamide；N-[3-[3-[(1,4-dioxido-1,2,4-benzotriazine-1,4-diium-3-yl)amino]propyl-methylamino]propyl]-2-pyridin-4-ylquinoline-8-carboxamide
• 化学式: C₂₉H₃₀N₈O₃
• 分子量: 538.609
• InChiKey: YGMODLDDQFSQBN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-chloro-1,2,4-benzotriazine 1-oxide 在 ammonium hydroxide 、 双氧水 、 三乙胺 、 三氟乙酸酐 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 乙腈 为溶剂， 反应 236.0h， 生成 N-{3-[{3-[(1,4-dioxido-1,2,4-benzotriazin-3-yl)amino]propyl}(methyl)amino]propyl}-2-(4-pyridyl)-8-quinolinecarboxamide
  参考文献：
  名称：

  DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides:  Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine

  摘要：

  Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K-DNA) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M-1 (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pKa. The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C-10), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C-10(aerobic)/C-10(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (> 167 and 400) values. There was a strong correlation between K-DNA and hypoxic cytotoxicity but no correlation between K-DNA and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC50 assays, showed similar relationships with a correlation between KDNA and hypoxic cytotoxicity but no correlation between KDNA and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.

  DOI：

  10.1021/jm030399c

文献信息

• [EN] DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY<br/>[FR] 1,4-DIOXIDES DE BENZOTRIAZINE CIBLEES SUR ADN ET LEUR UTILISATION DANS LE TRAITEMENT DU CANCER
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2004026846A1

  公开（公告）日：2004-04-01

  The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及以DNA为靶标的1,2,4-苯并三氮唑-1,4-二氧化物及相关类似物，其制备方法，以及它们作为针对缺氧选择性药物和放射增敏剂在癌症治疗中的应用，无论是单独使用还是与放射线和/或其他抗癌药物结合使用。
• Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy
  申请人：Brown Martin J.

  公开号：US20070191372A1

  公开（公告）日：2007-08-16

  The present invention relates to DNA-targeted 1,2,4-benzotriazine-1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及以DNA为靶点的1,2,4-苯并三氮唑-1,4-二氧化物及其相关类似物，其制备方法以及它们作为低氧选择性药物和放射增敏剂在癌症治疗中的使用，可以单独使用或与放射线和/或其他抗癌药物结合使用。
• Novel 1,2,4-benzotriazine-1,4-dioxides
  申请人：Denny Alexander William

  公开号：US20070197534A1

  公开（公告）日：2007-08-23

  The present invention provides a simplified set of characteristics that can be used to select 1,2,4 benzotriazine 1,4 dioxide compounds (TPZ analogues) with therapeutic activity against hypoxic cells in human tumour xenografts, and to further provide a novel class of 1,2,4-benzotriazine-1,4-dioxides (TPZ analogues) with predicted in vivo activity against tumours, to their preparation, and to their use as hypoxia-selective cytotoxic drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明提供了一组简化的特征，可用于选择对人类肿瘤异种移植物中的低氧细胞具有治疗活性的1,2,4-苯并三氮唑-1,4-二氧化物化合物（TPZ类似物），并进一步提供一种新型的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），预测其对肿瘤的体内活性，以及它们的制备和作为低氧选择性细胞毒性药物和放射增敏剂用于癌症治疗，单独或与放射线和/或其他抗癌药物联合使用。
• US7816521B2
  申请人：——

  公开号：US7816521B2

  公开（公告）日：2010-10-19
• DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides:  Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine
  作者：Michael P. Hay、Frederik B. Pruijn、Swarna A. Gamage、H. D. Sarath Liyanage、Mary S. Kovacs、Adam V. Patterson、William R. Wilson、J. Martin Brown、William A. Denny

  DOI：10.1021/jm030399c

  日期：2004.1.1

  Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K-DNA) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M-1 (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pKa. The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C-10), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C-10(aerobic)/C-10(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (> 167 and 400) values. There was a strong correlation between K-DNA and hypoxic cytotoxicity but no correlation between K-DNA and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC50 assays, showed similar relationships with a correlation between KDNA and hypoxic cytotoxicity but no correlation between KDNA and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.