ethyl (S)-1-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-fluoro-4-oxo-4H-pyrido[3,2,1-kl]naphtho[1,2-g]-phenoxazine-5-carboxylate | 500005-00-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: ethyl (S)-1-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-fluoro-4-oxo-4H-pyrido[3,2,1-kl]naphtho[1,2-g]-phenoxazine-5-carboxylate
• 英文别名: ethyl 19-fluoro-18-[(3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidin-1-yl]-22-oxo-16-oxa-1-azahexacyclo[15.7.1.02,15.04,13.07,12.021,25]pentacosa-2(15),3,5,7,9,11,13,17(25),18,20,23-undecaene-23-carboxylate
• CAS: 500005-00-5
• 化学式: C₃₅H₃₂FN₃O₆
• 分子量: 609.654
• InChiKey: PARPTHGEGMVZQY-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  45
• 可旋转键数：
  7
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  97.4
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ethyl (S)-1-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-fluoro-4-oxo-4H-pyrido[3,2,1-kl]naphtho[1,2-g]-phenoxazine-5-carboxylate 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 生成
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Series of Fluoroquinoanthroxazines with Contrasting Dual Mechanisms of Action against Topoisomerase II and G-Quadruplexes

  摘要：

  Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.

  DOI：

  10.1021/jm0203377
• 作为产物：
  描述：

  左氧氟单酯 在 吡啶 、 乙酸酐 、 碳酸氢钠 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 ethyl (S)-1-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-fluoro-4-oxo-4H-pyrido[3,2,1-kl]naphtho[1,2-g]-phenoxazine-5-carboxylate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Series of Fluoroquinoanthroxazines with Contrasting Dual Mechanisms of Action against Topoisomerase II and G-Quadruplexes

  摘要：

  Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.

  DOI：

  10.1021/jm0203377

文献信息

• Design, Synthesis, and Biological Evaluation of a Series of Fluoroquinoanthroxazines with Contrasting Dual Mechanisms of Action against Topoisomerase II and G-Quadruplexes
  作者：Mu-Yong Kim、Wenhu Duan、Mary Gleason-Guzman、Laurence H. Hurley

  DOI：10.1021/jm0203377

  日期：2003.2.1

  Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.