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Fe II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes
Author(s) -
Malina Jaroslav,
Kostrhunova Hana,
Scott Peter,
Brabec Viktor
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202101388
Subject(s) - g quadruplex , dna , nucleic acid , microbiology and biotechnology , chemistry , primer (cosmetics) , biology , biochemistry , stereochemistry , organic chemistry
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.