FeII 金属螺旋可稳定 DNA G-四链体并下调 G-四链体调节的癌基因的表达,Chemistry - A European Journal

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FeII 金属螺旋可稳定 DNA G-四链体并下调 G-四链体调节的癌基因的表达
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2021-05-28 , DOI: 10.1002/chem.202101388
Jaroslav Malina ₁ , Hana Kostrhunova ₁ , Peter Scott ₂ , Viktor Brabec ₁

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已在许多原癌基因的启动子区域内鉴定出 DNA G-四链体 (G4)。因此，G4s 代表了癌症治疗的有吸引力的靶点，而作为 G4 结合剂的新药的设计和开发是药物化学中一个非常活跃的领域。在这里，分子生物物理学和生物学方法被用来研究手性金属螺旋与由人类端粒序列( hTelo )和在c-MYC和c-KIT的启动子区域原癌基因。我们表明，所研究的水相容性、光学纯金属螺旋体是由简单的非肽有机成分围绕 Fe ^II离子自组装制成的，并表现出模拟自然系统的生物活性，与 G4 DNA 具有高亲和力，而对双链体的亲和力则低得多。脱氧核糖核酸。值得注意的是，发现含有间二甲苯基桥 ( 5b ) 的金属螺旋的两种对映异构体通过稳定包含c-myc和c-kit2 G4形成序列的模板链中形成的 G4 结构来有效抑制Taq DNA 聚合酶催化的引物延伸. 此外，5 b的两种对映异构体均下调人胚胎肾细胞中 mRNA 和蛋白质水平的c-MYC和c-KIT癌基因。由于金属螺旋体还结合替代核酸结构，它们有望成为潜在的多靶点药物。

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FeII Metallohelices Stabilize DNA G-Quadruplexes and Downregulate the Expression of G-Quadruplex-Regulated Oncogenes

DNA G-quadruplexes (G4s) have been identified within the promoter regions of many proto-oncogenes. Thus, G4s represent attractive targets for cancer therapy, and the design and development of new drugs as G4 binders is a very active field of medicinal chemistry. Here, molecular biophysics and biology methods were employed to investigate the interaction of chiral metallohelices with a series of four DNA G4s (hTelo, c-myc, c-kit1, c-kit2) that are formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT proto-oncogenes. We show that the investigated water-compatible, optically pure metallohelices, which are made by self-assembly of simple nonpeptidic organic components around Fe^II ions and exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity to duplex DNA. Notably, both enantiomers of a metallohelix containing a m-xylenyl bridge (5 b) were found to effectively inhibit primer elongation catalyzed by Taq DNA polymerase by stabilizing G4 structures formed in the template strands containing c-myc and c-kit2 G4-forming sequences. Moreover, both enantiomers of 5 b downregulated the expression of c-MYC and c-KIT oncogenes in human embryonic kidney cells at mRNA and protein levels. As metallohelices also bind alternative nucleic acid structures, they hold promise as potential multitargeted drugs.

更新日期：2021-05-28

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