6-chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1H,7H-pyrimido [5,6,1-de]acridine-1,3,7-trione | 155995-69-0

• 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: 6-chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1H,7H-pyrimido [5,6,1-de]acridine-1,3,7-trione
• 英文别名: 10-Chloro-15-[2-(dimethylamino)ethyl]-1,15-diazatetracyclo[7.7.1.02,7.013,17]heptadeca-2,4,6,9,11,13(17)-hexaene-8,14,16-trione
• CAS: 155995-69-0
• 化学式: C₁₉H₁₆ClN₃O₃
• 分子量: 369.807
• InChiKey: YEVMBRBTFGQAMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  60.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1H,7H-pyrimido [5,6,1-de]acridine-1,3,7-trione 在 三乙胺 作用下， 以 乙二醇乙醚 为溶剂， 反应 4.0h， 生成 15-[2-(Dimethylamino)ethyl]-10-[3-[methyl-[3-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]propylamino]-1,15-diazatetracyclo[7.7.1.02,7.013,17]heptadeca-2,4,6,9,11,13(17)-hexaene-8,14,16-trione
  参考文献：
  名称：

  Synthesis and Biological Evaluation of New Asymmetrical Bisintercalators as Potential Antitumor Drugs

  摘要：

  The good results obtained in the past decade with various types of potential bisintercalating agents, e. g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 ( Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t ( Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.

  DOI：

  10.1021/jm0606793
• 作为产物：
  描述：

  1-氯-9,10-二氢-9-氧代-4-吖啶羧酸 在 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 1.0h， 生成 6-chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1H,7H-pyrimido [5,6,1-de]acridine-1,3,7-trione
  参考文献：
  名称：

  Synthesis of (Dialkylamino)alkyl-Disubstituted Pyrimido[5,6,1-de]acridines, a Novel Group of Anticancer Agents Active on a Multidrug Resistant Cell Line

  摘要：

  A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3,7-trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in, vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.

  DOI：

  10.1021/jm00017a013

文献信息

• Rational Design, Synthesis, and Biological Evaluation of Bis(pyrimido[5,6,1-<i>de</i>]acridines) and Bis(pyrazolo[3,4,5-<i>kl</i>]acridine-5-carboxamides) as New Anticancer Agents
  作者：Ippolito Antonini、Paolo Polucci、Amelia Magnano、Silvia Sparapani、Sante Martelli

  DOI：10.1021/jm049706k

  日期：2004.10.1

  des) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4;

  嘧啶并[5,6,1-de] ac啶7和吡唑并[3,4,5-kl] ac啶酰胺8的良好结果促使我们合成了两个新的双a啶衍生物系列：bis（pyrimidoacridines） 5和双（吡唑并r羧酰胺）6。化合物5也可被视为双（ac啶-4-甲酰胺）3的环化衍生物，化合物6也可被视为双（ac啶-4-羧酰胺）4的环化衍生物。这些化合物的性质已使用荧光技术进行了检查。结果表明：（i）目标化合物是优良的DNA配体；（ii）双衍生物5和6比相应的单体7和8具有更高的DNA亲和力；（iii）新的bis 5和6的结合效率始终不如相关的bis（acridine-4-carboxamides）3和4。（iv）在系列5和系列6中，在某些情况下明显的，显着的，可以注意到倾向于与富含AT的双链体结合。描述了这些衍生物对人结肠腺癌细胞系（HT29）的体外细胞毒性作用，并将其与参考药物进行了比较。讨论了构效关系。我们可以
• 2,3-Dihydro-1<i>H</i>,7<i>H</i>-pyrimido[5,6,1-<i>d</i><i>e</i>]acridine-1,3,7-trione Derivatives, a Class of Cytotoxic Agents Active on Multidrug-Resistant Cell Lines:  Synthesis, Biological Evaluation, and Structure−Activity Relationships
  作者：Ippolito Antonini、Paolo Polucci、Lloyd R. Kelland、Ernesto Menta、Nicoletta Pescalli、Sante Martelli

  DOI：10.1021/jm9805586

  日期：1999.7.1

  corresponding 6-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward eight tumor cell lines, including human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR

  通过以下方法制备了一系列可插入DNA的潜在抗肿瘤药：（氨基）烷基取代的2,3-二氢-1H，7H-嘧啶基[5,6,1-de] ac啶-1,3,7-三酮。相应的6-氯衍生物与合适的ω-氨基烷基胺进行氨解。这些化合物的非共价DNA结合特性已使用荧光技术进行了检查。这些衍生物对八种肿瘤细胞系的体外细胞毒性潜能，包括人结肠腺癌（HT29，LoVo敏感和LoVo / Dx（对阿霉素耐药））和人卵巢癌（对A2780敏感，对A2780cisR（对顺铂耐药），CH1，CH1cisR描述了顺铂（顺铂耐药）和SKOV-3细胞，并将其与参考药物进行了比较。对于几乎所有目标化合物，其细胞毒活性通常与观察到的DNA亲和力平行。已经发现有趣的结构-活性关系。还计算了辛醇/水分配系数，但与细胞毒性值或抗药性指数均无关。已鉴定出三种具有高度DNA亲和力的类似物9和15f，15h，具有广泛的细胞毒性活性。
• 2,6-Di(ω-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-<i>mn</i>]pyrimido[5,6,1-<i>de</i>]acridine-5,7-diones:  Novel, Potent, Cytotoxic, and DNA-Binding Agents
  作者：Ippolito Antonini、Paolo Polucci、Amelia Magnano、Barbara Gatto、Manlio Palumbo、Ernesto Menta、Nicoletta Pescalli、Sante Martelli

  DOI：10.1021/jm011004x

  日期：2002.1.1

  DNA-binding agents with potential antitumor activities bearing two cationic side chains, the 2,6-di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4a-r), have been prepared either by reaction of the appropriate 2-(omega-aminoalkyl)-6-chloro-2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione with the appropriate (omega-aminoalkyl)hydrazine or by cyclization of the requisite N-6,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-6-carboxamide with phosgene. In vitro cytotoxic properties of these derivatives against three human colon adenocarcinoma cell lines (HT29, LoVo, and LoVo/Dx) and against some cell lines of the NCI panel are described and compared to that of reference drugs. Some of the new compounds showed outstanding potency while lacking cross-resistance with anthracyclines. Structure-activity relationships are discussed, and a mechanistic analysis is performed using the COMPARE procedure. The mechanism and efficiency of noncovalent DNA binding of these compounds are examined using gel electrophoresis and fluorometric techniques. The 2,6-di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4) constitute a new class of potent, cytotoxic DNA-binding agents not cross-resistant with doxorubicin.
• Synthesis of (Dialkylamino)alkyl-Disubstituted Pyrimido[5,6,1-de]acridines, a Novel Group of Anticancer Agents Active on a Multidrug Resistant Cell Line
  作者：Ippolito Antonini、Donatella Cola、Paolo Polucci、Maria Bontemps-Gracz、Edward Borowski、Sante Martelli

  DOI：10.1021/jm00017a013

  日期：1995.8

  A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3,7-trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in, vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
• Synthesis and Biological Evaluation of New Asymmetrical Bisintercalators as Potential Antitumor Drugs
  作者：Ippolito Antonini、Giorgio Santoni、Roberta Lucciarini、Consuelo Amantini、Silvia Sparapani、Amelia Magnano

  DOI：10.1021/jm0606793

  日期：2006.11.30

  The good results obtained in the past decade with various types of potential bisintercalating agents, e. g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 ( Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t ( Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.