3-(9-acridinylamino)-5-hydroxymethylaniline-N-succinic acid monocarboxamide | 154310-46-0

• 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: 3-(9-acridinylamino)-5-hydroxymethylaniline-N-succinic acid monocarboxamide
• 英文别名: 4-[3-(Acridin-9-ylamino)-5-(hydroxymethyl)anilino]-4-oxobutanoic acid
• CAS: 154310-46-0
• 化学式: C₂₄H₂₁N₃O₄
• 分子量: 415.448
• InChiKey: YNISWACPPPLCTA-UHFFFAOYSA-N

物化性质

• 熔点：
  235-236 °C
• 沸点：
  717.4±60.0 °C(predicted)
• 密度：
  1.425±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-amino-N-[5-[2-(dimethylamino)ethylcarbamoyl]-1-methylpyrrol-3-yl]-1-methylpyrrole-2-carboxamide 、 3-(9-acridinylamino)-5-hydroxymethylaniline-N-succinic acid monocarboxamide 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 以54%的产率得到N-[2-(dimethylamino)ethyl]-1-methyl-4-[1-methyl-4-[[[3-(9-acridinylamino)-5-hydroxymethylanilino]carbonylpropanoyl]amino]pyrrole-2-carboxamido]-pyrrole-2-carboxamide
  参考文献：
  名称：

  Antitumor AHMA Linked to DNA Minor Groove Binding Agents:  Synthesis and Biological Evaluation

  摘要：

  DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bis-benzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II.

  DOI：

  10.1021/jm0200714
• 作为产物：
  描述：

  [3-(吖啶-9-基氨基)-5-氨基苯基]甲醇 在 4-二甲氨基吡啶 、 sodium methylate 作用下， 以 吡啶 、 甲醇 为溶剂， 反应 51.0h， 生成 3-(9-acridinylamino)-5-hydroxymethylaniline-N-succinic acid monocarboxamide
  参考文献：
  名称：

  具有长的半衰期和有效的抗肿瘤活性的9-取代的cr啶衍生物：合成与结构活性关系。

  摘要：

  合成了一系列插入DNA的9-苯胺基cr啶，即9-苯氧基ac啶，9-（苯硫基）ac啶和9-（3'，5'-二取代的苯胺基）ac啶，它们可能对DNA拓扑异构酶II具有抑制作用。与氨水扁桃碱（m-AMSA）不同，这些试剂旨在避免氧化代谢途径。因此，预期这些a啶衍生物在血浆中具有长的半衰期。发现9-苯氧基ac啶和9-（苯硫基）ac啶对培养的小鼠白血病L1210和人类白血病HL-60细胞均具有中等细胞毒性。在9-（3'，5'-二取代的苯胺基）ac啶中，发现3-（9-ac啶基氨基）-5-（羟甲基）苯胺（AHMA）是有效的拓扑异构酶II抑制剂，在体外和体外均表现出显着的抗肿瘤功效体内。分别以10、10和5 mg / kg（QD x 4，ip）AHMA，VP-16和m-AMSA化疗的实体瘤小鼠，与VP-相比，AHMA减少的肿瘤体积更大16或m-AMSA用于E0771乳腺腺癌和B-16黑色素瘤。对于刘易斯肺癌

  DOI：

  10.1021/jm00017a006

文献信息

• 9-Substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships
  作者：Tsann-Long Su、Ting-Chao Chou、Joong Young Kim、Jai-Tung Huang、Grazyna Ciszewska、Wu-Yun Ren、Grenys M. Otter、Francis M. Sirotnak、Kyoichi A. Watanabe

  DOI：10.1021/jm00017a006

  日期：1995.8

  in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA

  合成了一系列插入DNA的9-苯胺基cr啶，即9-苯氧基ac啶，9-（苯硫基）ac啶和9-（3'，5'-二取代的苯胺基）ac啶，它们可能对DNA拓扑异构酶II具有抑制作用。与氨水扁桃碱（m-AMSA）不同，这些试剂旨在避免氧化代谢途径。因此，预期这些a啶衍生物在血浆中具有长的半衰期。发现9-苯氧基ac啶和9-（苯硫基）ac啶对培养的小鼠白血病L1210和人类白血病HL-60细胞均具有中等细胞毒性。在9-（3'，5'-二取代的苯胺基）ac啶中，发现3-（9-ac啶基氨基）-5-（羟甲基）苯胺（AHMA）是有效的拓扑异构酶II抑制剂，在体外和体外均表现出显着的抗肿瘤功效体内。分别以10、10和5 mg / kg（QD x 4，ip）AHMA，VP-16和m-AMSA化疗的实体瘤小鼠，与VP-相比，AHMA减少的肿瘤体积更大16或m-AMSA用于E0771乳腺腺癌和B-16黑色素瘤。对于刘易斯肺癌
• Antitumor AHMA Linked to DNA Minor Groove Binding Agents:  Synthesis and Biological Evaluation
  作者：Kamesh Rastogi、Jang-Yang Chang、Wen-Yu Pan、Ching-Huang Chen、Ting-Chao Chou、Li-Tzong Chen、Tsann-Long Su

  DOI：10.1021/jm0200714

  日期：2002.9.1

  DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bis-benzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II.