acridine-4-carboxylic acid imidazolide | 206531-90-0

• 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: acridine-4-carboxylic acid imidazolide
• 英文别名: 4-(1H-imidazol-1-ylcarbonyl)acridine；acridine-4-carboxamide；4-(1H-imidazol-1-ylcarbonyl) acridine；acridin-4-yl(imidazol-1-yl)methanone
• CAS: 206531-90-0
• 化学式: C₁₇H₁₁N₃O
• 分子量: 273.294
• InChiKey: CTIMUFUEAPUEQS-UHFFFAOYSA-N

物化性质

• 沸点：
  539.4±42.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  47.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  acridine-4-carboxylic acid imidazolide 在 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 32.0h， 生成 N-[3-({3-[(1,4-dioxido-1,2,4-benzotriazin-3-yl)amino]propyl}amino)propyl]-4-acridinecarboxamide
  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
• 作为产物：
  描述：

  4-羧基-9-茚酮 在 mercury amalgam 作用下， 以 1,4-二氧六环 为溶剂， 反应 5.5h， 生成 acridine-4-carboxylic acid imidazolide
  参考文献：
  名称：

  Design, synthesis, and DNA sequence selectivity of formaldehyde-mediated DNA-adducts of the novel N -(4-aminobutyl) acridine-4-carboxamide

  摘要：

  A novel derivative of the anti-tumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) was prepared by reduction of 9-oxoacridan-4-carboxylic acid to acridine-4-carboxylic acid with subsequent conversion to N-(4-aminobutyl)acridine-4-carboxamide (C4-DACA). Molecular modeling studies suggested that a DACA analogue comprising a side chain length of four carbons was optimal to form formaldehyde-mediated drug-DNA adducts via the minor groove. An in vitro transcription assay revealed that formaldehyde-mediated C4-DACA-DNA adducts selectively formed at CpG and CpA dinucleotide sequences, which is strikingly similar to that of formaldehyde-activated anthracenediones such as pixantrone. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.10.062

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。
• [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。
• 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。
• Synthesis and evaluation of unsymmetrical bis(arylcarboxamides) designed as topoisomerase-Targeted anticancer drugs
  作者：Julie A Spicer、Swarna A Gamage、Graeme J Finlay、William A Denny

  DOI：10.1016/s0968-0896(01)00249-8

  日期：2002.1

  Symmetrical dimers of lipophilic intercalating chromophores linked by cation-containing chains have recently been shown to have broad-spectrum in vivo anticancer activity. We report the preparation and evaluation of a series of both symmetric and unsymmetric dimers of a variety of intercalating chromophores of varied DNA binding strength, including naphthalimides, acridines, phenazines, oxanthrenes and 2-phenylquinolines. The unsymmetrical dimers were prepared by sequential coupling of the chromophores to linkers with selectively protected primary terminal amines to ensure high yields and unequivocal product. Protection of the internal (secondary) amines as BOC derivatives was used to ensure complete structural specificity, and was also an aid to the purification of these very polar compounds. The growth inhibitory abilities (as IC50 values) of the compounds in a range of cell lines showed that the nature of the linker chain was important, and independent of the nature of the chromophore, with compounds containing the dicationic linker [-(CH2)(2)NH(CH2)(2)NH(CH2)(2)-] being on average 30-fold more potent than the corresponding compounds containing the monocationic linker [-(CH2)(3)NMe(CH2)(3)-]. However, the chromophores also play a role in determining biological activity, with the cytotoxicities of symmetric and unsymmetric dicationic dimers correlating with the overall DNA binding abilities of the chromophores. (C) 2001 Elsevier Science Ltd. All rights reserved.
• 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