9-(dimethylamino)phenazine-1-carboxylic acid | 206530-99-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 9-(dimethylamino)phenazine-1-carboxylic acid
• 英文别名: 9-(Dimethylamino)-1-phenazinecarboxylic acid
• CAS: 206530-99-6
• 化学式: C₁₅H₁₃N₃O₂
• 分子量: 267.287
• InChiKey: MQNQJWCQFANIMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  66.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-(dimethylamino)phenazine-1-carboxylic acid 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 9-Dimethylamino-phenazine-1-carboxylic acid (2-dimethylamino-ethyl)-amide
  参考文献：
  名称：

  Phenazine-1-carboxamides: Structure–cytotoxicity relationships for 9-substituents and changes in the H-bonding pattern of the cationic side chain

  摘要：

  A series of phenazine-1-carboxamides were prepared, including variations in both chromophore substituents and the nature of the cationic side chain. The novel side-chain analogues were prepared from the corresponding phenazine-1-carboxylic acids via Schmidt conversion to the 1-amines and from the corresponding 1-halides. Structure-cytotoxicity relationships for these compounds in a panel of tumor cell lines showed that there is very limited scope for variation of the structure of the 1-carboxamide side chain, consistent with the recent Structural model of flow tricyclic carboxamides bind to DNA. There was generally little difference in IC(50)s between parent and P-glycoprotein expressing cell lines, suggesting that most of the compounds are not affected by the presence of this efflux pump. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.09.032
• 作为产物：
  描述：

  9-fluorophenazine-1-carboxylic acid 、 二甲胺 以 水 为溶剂， 反应 3.0h， 以95%的产率得到9-(dimethylamino)phenazine-1-carboxylic acid
  参考文献：
  名称：

  Bis(phenazine-1-carboxamides):  Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs

  摘要：

  Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH2)(3)NMe(CH2)(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia; The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g,, Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 mu M and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 mu M, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines ton average 9.5-fold more active in the HT29 line than in the cell line, panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.

  DOI：

  10.1021/jm990423f

文献信息

• [EN] BIS(ACRIDINECARBOXAMIDE) AND BIS(PHENAZINECARBOXAMIDE) AS ANTITUMOUR AGENTS<br/>[FR] (BIS)ACRIDINECARBOXAMIDE ET (BIS)PHENAZINECARBOXAMIDE UTILISES EN TANT QU'AGENTS ANTITUMORAUX
  申请人：XENOVA LIMITED

  公开号：WO1998017650A1

  公开（公告）日：1998-04-30

  (EN) A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I), wherein each X, which may be the same or different in a given molecule, is -CH= or -N= each of R1 to R4 which may be the same or different, H, C1-C4 alkyl, OH, SH, NH2, C1-C4 alkoxy, aryloxy, NHR, N(R)2, SR, SO2R wherein R is C1-C4 alkyl, CF3, NO2 or halogen, or R1 and R2 together form a methylenedioxy group; each of R5 and R6, which may be the same or different, is H or C1-C4 alkyl; Z is (CH2)n, (CH2)nO(CH2)n, (CH2)nN(R7) (CH2)n, (CH2)nN(R7) (CH2)mN(R7) (CH2)n or (CH2)nN(CH2CH2)2N(CH2)n wherein R7 is H or C1-C4 alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; has activity as an antitumour and antibacterial agent.(FR) L'invention concerne un composé qui est dérivé de (bis)acridinecarboxamide et de (bis)phénazinecarboxamide de formule (I), dans laquelle chaque X, qui peut être identique ou différent dans une molécule donnée, représente -CH= ou -N=, chacun des R1 à R4, qui peuvent être identiques ou différents, représentant H, un alkyle en C1-C4, OH, SH, NH2, un alkoxy en C1-C4, un aryloxy, NHR; N(R)2, SR, SO2R, R représentant un alkyle en C1-C4, CF3, NO2 ou halogène, ou R1 et R2 formant ensemble un groupe méthylènedioxy; chacun des R5 et R6, qui peuvent être identiques ou différents, représentant H ou un alkyle en C1-C4; Z représente (CH2)n, (CH2)nO(CH2)n, (CH2)nN(R7) (CH2)nN(R7) (CH2)mN(R7) (CH2)n ou (CH2)nN(CH2CH2)2N(CH2)n, R7 représentant H ou un alkyle en C1-C4, et n et m, qui peuvent être identiques ou différents, représentant chacun un nombre entier allant de 1 à 4; ou un sel d'addition d'acide pharmaceutiquement acceptable, ou un N-oxyde dudit sel; présente une activité en tant qu'agent antitumoral et antibactérien.

  一种化合物，其为公式(I)的双(吖啶甲酰胺)或双(菲嗪甲酰胺)衍生物，其中每个X在给定分子中可以相同或不同，为-CH=或-N=，每个R1到R4可以相同或不同，为H、C1-C4烷基、OH、SH、NH2、C1-C4烷氧基、芳氧基、NHR、N(R)2、SR、SO2R，其中R为C1-C4烷基、CF3、NO2或卤素，或者R1和R2组成一个亚甲二氧基基团；每个R5和R6可以相同或不同，为H或C1-C4烷基；Z为(CH2)n、(CH2)nO(CH2)n、(CH2)nN(R7)(CH2)n、(CH2)nN(R7)(CH2)mN(R7)(CH2)n或(CH2)nN(CH2CH2)2N(CH2)n，其中R7为H或C1-C4烷基，n和m可以相同或不同，均为1到4的整数；或其药学上可接受的酸加盐或N-氧化物；具有抗肿瘤和抗菌活性。
• Bis(acridinecarboxamide) and bis(phenazinecarboxamide) as antitumor
  申请人：Xenova Limited

  公开号：US06114332A1

  公开（公告）日：2000-09-05

  A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I): ##STR1## wherein each X, which may be the same or different in a given molecule, is --CH.dbd. or --N.dbd. each of R.sub.1 to R.sub.4 which may be the same or different, H, C.sub.1 -C.sub.4 alkyl, OH, SH, NH.sub.2, C.sub.1 -C.sub.4 alkoxy, aryloxy, NHR, N(R).sub.2, SR, SO.sub.2 R wherein R is C.sub.1 -C.sub.4 alkyl, CF.sub.3, NO.sub.2 or halogen, or R.sub.1 and R.sub.2 together form a methylenedioxy group; each of R.sub.5 and R.sub.6, which may be the same or different, is H or C.sub.1 -C.sub.4 alkyl; Z is (CH.sub.2).sub.n, (CH.sub.2).sub.n O(CH.sub.2).sub.n, (CH.sub.2).sub.n N(R.sub.7)(CH.sub.2).sub.n, (CH.sub.2).sub.n N(R.sub.7)(CH.sub.2).sub.m N(R.sub.7)(CH.sub.2).sub.n or (CH.sub.2).sub.n N(CH.sub.2 CH.sub.2).sub.2 N(CH.sub.2).sub.n wherein R.sub.7 is H or C.sub.1 -C.sub.4 alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; has activity as an antitumor and antibacterial agent.

  化合物为公式（I）的双（吖啶羧酰胺）或双（菲嗪羧酰胺）衍生物：其中每个X在给定的分子中可能相同或不同，为--CH.dbd.或--N.dbd.；每个R.sub.1到R.sub.4在给定的分子中可能相同或不同，为H、C.sub.1-C.sub.4烷基、OH、SH、NH.sub.2、C.sub.1-C.sub.4烷氧基、芳氧基、NHR、N（R）.sub.2、SR、SO.sub.2R，其中R为C.sub.1-C.sub.4烷基、CF.sub.3、NO.sub.2或卤素，或R.sub.1和R.sub.2共同形成一个亚甲二氧基基团；每个R.sub.5和R.sub.6，可能相同或不同，为H或C.sub.1-C.sub.4烷基；Z为（CH.sub.2）.sub.n、（CH.sub.2）.sub.n O（CH.sub.2）.sub.n、（CH.sub.2）.sub.n N（R.sub.7）（CH.sub.2）.sub.n、（CH.sub.2）.sub.n N（R.sub.7）（CH.sub.2）.sub.m N（R.sub.7）（CH.sub.2）.sub.n或（CH.sub.2）.sub.n N（CH.sub.2CH.sub.2）.sub.2N（CH.sub.2）.sub.n，其中R.sub.7为H或C.sub.1-C.sub.4烷基，n和m可能相同或不同，均为1至4的整数；或其药学上可接受的酸加盐或N-氧化物；具有抗肿瘤和抗菌活性。
• BIS(ACRIDINECARBOXAMIDE) AND BIS(PHENAZINECARBOXAMIDE) AS ANTITUMOUR AGENTS
  申请人：XENOVA LIMITED

  公开号：EP0934278A1

  公开（公告）日：1999-08-11
• US6114332A
  申请人：——

  公开号：US6114332A

  公开（公告）日：2000-09-05
• Bis(phenazine-1-carboxamides):  Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs
  作者：Julie A. Spicer、Swarna A. Gamage、Gordon W. Rewcastle、Graeme J. Finlay、David J. A. Bridewell、Bruce C. Baguley、William A. Denny

  DOI：10.1021/jm990423f

  日期：2000.4.6

  Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH2)(3)NMe(CH2)(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia; The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g,, Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 mu M and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 mu M, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines ton average 9.5-fold more active in the HT29 line than in the cell line, panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.