Abstract

DNA G-quadruplexes (G4s) were 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, we employed methods of molecular biophysics and biology 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 made by self-assembly of simple nonpeptidic organic components around Fe(II) ions, which exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity towards duplex DNA. Notably, both enantiomers of metallohelix containing m -xylenyl bridge ( 5b ) were found to be effective inhibitors of 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 5b down-regulated 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 multi-targeted drugs.

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