4-methoxy-9-chloroacridan-5-methylcarboxamide | 88377-34-8

• 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: 4-methoxy-9-chloroacridan-5-methylcarboxamide
• 英文别名: 9-chloro-4-methoxy-5-(N-methylcarbamoyl)acridine；N-methyl-4-methoxy-9-chloroacridine-5-carboxamide；9-chloro-4-methoxy-N-methyl-5-acridinecarboxamide；9-chloro-4-methoxy-5-<(methylamino)carbonyl>acridine；9-Chloro-5-methoxy-N-methylacridine-4-carboxamide
• CAS: 88377-34-8
• 化学式: C₁₆H₁₃ClN₂O₂
• 分子量: 300.744
• InChiKey: LVWYYMVQAKBFAS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-methoxy-9-chloroacridan-5-methylcarboxamide 在 吡啶 、 N-methoxymorpholine 作用下， 以 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.25h， 生成 [3-Hydroxymethyl-5-(4-methoxy-5-methylcarbamoyl-acridin-9-ylamino)-phenyl]-carbamic acid ethyl ester; hydrochloride
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Potential Anticancer Agents:  Alkylcarbamates of 3-(9-Acridinylamino)-5-hydroxymethylaniline

  摘要：

  A series of potential 9-anilinoacridine antitumor agents, 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives with monosubstituent at C4' and disubstituents at C4' and C5' of the acridine ring and their alkylcarbamates, were synthesized for evaluation of their antitumor activity. A structure-activity relationship (SAR) study showed that the AHMA-alkylcarbamates were more potent than their corresponding parent AHMA compounds. In addition, the cytotoxicity of the AHMA-alkylcarbamate decreased with increasing length and size of the alkyl function. Among these compounds, AHMA-ethylcarbamate (18) and 4'-methyl-5'-dimethylaminoethylcarboxamido-AHMA-ethylcarbamate (34) possess potent cytotoxicity on the inhibition of human leukemic HL-60 cell growth in culture. Further in vivo studies of these compounds displayed significant anticancer therapeutic effects in mice bearing sarcoma 180, Lewis lung carcinoma, and P388 leukemia.

  DOI：

  10.1021/jm9901226
• 作为产物：
  描述：

  5-Methoxy-9-oxo-9,10-dihydro-acridine-4-carboxylic acid methylamide 在 氯化亚砜 作用下， 生成 4-methoxy-9-chloroacridan-5-methylcarboxamide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Potential Anticancer Agents:  Alkylcarbamates of 3-(9-Acridinylamino)-5-hydroxymethylaniline

  摘要：

  A series of potential 9-anilinoacridine antitumor agents, 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives with monosubstituent at C4' and disubstituents at C4' and C5' of the acridine ring and their alkylcarbamates, were synthesized for evaluation of their antitumor activity. A structure-activity relationship (SAR) study showed that the AHMA-alkylcarbamates were more potent than their corresponding parent AHMA compounds. In addition, the cytotoxicity of the AHMA-alkylcarbamate decreased with increasing length and size of the alkyl function. Among these compounds, AHMA-ethylcarbamate (18) and 4'-methyl-5'-dimethylaminoethylcarboxamido-AHMA-ethylcarbamate (34) possess potent cytotoxicity on the inhibition of human leukemic HL-60 cell growth in culture. Further in vivo studies of these compounds displayed significant anticancer therapeutic effects in mice bearing sarcoma 180, Lewis lung carcinoma, and P388 leukemia.

  DOI：

  10.1021/jm9901226

文献信息

• Potential antitumor agents. 47. 3'-Methylamino analogs of amsacrine with in vivo solid tumor activity
  作者：Graham J. Atwell、Bruce C. Baguley、Graeme J. Finlay、Gordon W. Rewcastle、William A. Denny

  DOI：10.1021/jm00159a035

  日期：1986.9

  antileukemic agent amsacrine with a 3'-methylamino group provides a compound (3) with a broader spectrum of action, including in vivo activity against experimental solid tumors. The synthesis, physicochemical properties, and biological activity of a series of acridine-substituted analogues of 3 are described. The compounds show higher levels of DNA binding, water solubility, and in vivo solid tumor activity

  用3'-甲基氨基取代临床抗白血病药物氨苯磺酸的3'-甲氧基提供了具有更广谱作用的化合物（3），包括针对实验性实体瘤的体内活性。描述了一系列3的a啶取代的类似物的合成，理化性质和生物学活性。这些化合物显示出更高的DNA结合水平，水溶性和体内实体瘤活性（刘易斯肺癌），而其氨色林对应物更高。然而，a啶取代的结构-活性关系是不同的，其中3,5-二取代的3'-甲基氨基化合物显示出最高的活性（与4,5-二取代的氨ac碱类似物相比）。
• Potential antitumor agents. 40. Orally active 4,5-disubstituted derivatives of amsacrine
  作者：William A. Denny、Graham J. Atwell、Bruce C. Baguley

  DOI：10.1021/jm00369a021

  日期：1984.3

  5-disubstituted derivatives all showed high activity when administered ip against ip-implanted P-388, but activity varied widely when the compounds were given orally. 4-Methoxy and 4-carbamoyl derivatives proved essentially inactive, whereas 4-methyl and 4-methylcarbamoyl derivatives retained activity. Exceptional oral activity was shown by the 4-methyl-5-methylcarbamoyl derivative, making this amsacrine

  DNA嵌入剂amsacrine是治疗人类白血病和淋巴瘤的有效药物，但实体瘤活性极低。作为鉴定具有更广谱活性的类似物的第一步，对通过口服（po）和腹膜内（ip）途径给予的Amsacrine类似物的体内抗白血病（P-388）活性进行了比较。一系列的4-取代和4,5-二取代的衍生物在ip注射时对ip植入的P-388均显示出高活性，但是当口服给予化合物时，活性变化很大。事实证明4-甲氧基和4-氨基甲酰基衍生物基本上没有活性，而4-甲基和4-甲基氨基甲酰基衍生物保持活性。4-甲基-5-甲基氨基甲酰基衍生物显示出非凡的口服活性，使该氨溴萘衍生物值得进一步测试。
• Potential antitumor agents. 52. Carbamate analogs of amsacrine with in vivo activity against multidrug-resistant P388 leukemia
  作者：Gordon W. Rewcastle、Bruce C. Baguley、Graham J. Atwell、William A. Denny

  DOI：10.1021/jm00392a009

  日期：1987.9

  provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar

  对一系列与抗白血病药物氨苯磺酸有关的苯胺取代的9-苯胺基cr啶的研究表明，1'-氨基甲酸酯基团在体内对多药耐药的P388 / ADR白血病亚系提供增强的活性。由于针对这种抗药性肿瘤的活性具有重要的临床意义，因此在体内针对野生型和ADR /抗药性P388白血病以及Lewis肺实体瘤评估了一系列of啶取代的氨基甲酸酯衍生物。所有三个肿瘤细胞系的结构活性关系相似，其中3-卤代-5-甲基和3-卤代5-甲氧基化合物被证明是活性最高的。这种取代模式还提供了最高的DNA结合。此类化合物（尤其是3-氯-5-甲基和3-氯-5-甲氧基）对野生型P388和Lewis肺具有体内活性，其活性与先前开发的最佳氨水analogue类似物相当（治愈率超过50％） ，以及P388 / ADR活动。这项工作从根本上完成了amsacrine系列抗肿瘤药的开发。
• Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity
  作者：Graham J. Atwell、Gordon W. Rewcastle、Bruce C. Baguley、William A. Denny

  DOI：10.1021/jm00387a012

  日期：1987.4

  Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.
• ATWELL G. J.; BAGULEY B. C.; FINLAY G. J.; REWCASTLE G. W.; DENNY W. A., J. MED. CHEM., 29,(1986) N 9, 1769-1776
  作者：ATWELL G. J.、 BAGULEY B. C.、 FINLAY G. J.、 REWCASTLE G. W.、 DENNY W. A.

  DOI：——

  日期：——