...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.
【24h】

Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.

机译：发色团修饰的双萘二甲酰亚胺：DNA识别，拓扑异构酶抑制和两种单呋喃和双呋喃萘二甲酰亚胺的细胞毒性。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Bisnaphthalimides represent a promising group of DNA-targeted anticancer agents. In this series, the lead compounds elinafide and bisnafide have reached clinical trials, and the search for more potent analogues remains a priority. In the course of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the naphthalimide skeleton, different dimeric molecules containing two tetracyclic neutral DNA intercalating chromophores were synthesized. The naphthalimide unit has been fused to a benzene ring (azonafide derivatives), an imidazole, a pyrazine, or, as reported here, a furan ring which increases the planar surface of the chromophore and enhances its stacking properties. We report a detailed investigation of the DNA binding capacity of the dimeric molecule MCI3335 composed of two furonaphthalimide units connected by a 12 A long amino alkyl linker [(CH(2))(2)-NH-(CH(2))(3)-NH-(CH(2))(2)] identical to that of elinafide. Qualitative and quantitative binding studies, in particular using surface plasmon resonance, establish that the dimer binds considerably more tightly to DNA (up to 1000 times) than the corresponding monomer and exhibits a higher sequence selectivity for GC-rich sequences. DNase I footprinting experiments attest that the dimer, and to a lesser extent the monomer, preferentially intercalate at GC sites. The strong binding interaction between the drugs and DNA perturbs the relaxation of supercoiled DNA by topoisomerases, but the test compounds do not promote DNA cleavage by topoisomerase I or II. Despite the lack of poisoning effect toward topoisomerase II, MCI3335 displays a very high cytotoxicity toward CEM human leukemia cells, with an IC(50) in the low nanomolar range, approximately 4 times inferior to that of the reference drug elinafide. Confocal microscopy observations indicate that the monomer shows a stronger tendency to accumulate in the cell nuclei than the dimer. The extremely high cytotoxic potential of MCI3335 is attributed to its enhanced capacity to bind to DNA and to inhibit DNA synthesis, as evidenced by flow cytometry experiments using the BrdU assay. The results provide novel mechanistic information that furthers the understanding of the structure-activity relationships in the bisnaphthalimide series and identify MCI3335 as a novel lead compound for further preclinical investigations.
机译：双萘二甲酰亚胺代表了一组有前途的靶向DNA的抗癌药。在这个系列中，先导化合物依那那肽和比那非已经达到临床试验，寻找更有效的类似物仍然是当务之急。在旨在发现基于萘二甲酰亚胺骨架的新型抗肿瘤药物的药物化学程序中，合成了包含两个四环中性DNA嵌入发色团的不同二聚体分子。萘二甲酰亚胺单元已与苯环（氮杂afide衍生物），咪唑，吡嗪或呋喃环稠合，如此处报道的那样，该环增加了发色团的​​平面并增强了其堆叠性能。我们报告详细调查的二聚体分子MCI3335的DNA结合能力，该分子由两个呋喃邻苯二甲酰亚胺单元组成，它们由12 A长的氨基烷基接头[[CH（2））（2）-NH-（CH（2））（3 ）-NH-（CH（2））（2）]与elinafide相同。定性和定量结合研究，特别是使用表面等离振子共振的研究，确定二聚体与DNA的结合要比相应的单体紧密得多（最多1000倍），并且对富含GC的序列表现出更高的序列选择性。 DNase I足迹实验证明，二聚体和较小程度的单体优先插入GC位点。药物与DNA之间的强结合相互作用扰乱了拓扑异构酶对超螺旋DNA的松弛，但是受试化合物不促进拓扑异构酶I或II对DNA的切割。尽管缺乏对拓扑异构酶II的中毒作用，MCI3335对CEM人白血病细胞仍显示出很高的细胞毒性，其IC（50）处于低纳摩尔范围，比参考药物elinafide低约4倍。共聚焦显微镜观察表明，单体显示出比二聚体更强的在细胞核中积累的趋势。 MCI3335极高的细胞毒性潜力归因于其与DNA结合和抑制DNA合成的增强能力，如使用BrdU分析的流式细胞术实验所证明的。结果提供了新颖的机制信息，可进一步理解双萘二甲酰亚胺系列中的结构-活性关系，并将MCI3335鉴定为用于进一步临床前研究的新型先导化合物。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号