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Fe II metallohelices stabilize DNA G‐quadruplexes and downregulate the expression of G‐quadruplex‐regulated oncogenes
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Malina, Jaroslav, Kostrhunova, Hana, Scott, Peter and Brabec, Viktor (2021) Fe II metallohelices stabilize DNA G‐quadruplexes and downregulate the expression of G‐quadruplex‐regulated oncogenes. Chemistry – A European Journal, 27 (45). pp. 11682-11692. doi:10.1002/chem.202101388 ISSN 1521-3765.
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Official URL: http://doi.org/10.1002/chem.202101388
Abstract
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 FeII 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.
Item Type: | Journal Article | ||||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||
Library of Congress Subject Headings (LCSH): | Quadruplex nucleic acids, Cancer -- Treatment, Organometallic compounds, Oncogenes | ||||||
Journal or Publication Title: | Chemistry – A European Journal | ||||||
Publisher: | Wiley | ||||||
ISSN: | 1521-3765 | ||||||
Official Date: | 11 August 2021 | ||||||
Dates: |
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Volume: | 27 | ||||||
Number: | 45 | ||||||
Page Range: | pp. 11682-11692 | ||||||
DOI: | 10.1002/chem.202101388 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Reuse Statement (publisher, data, author rights): | This is the peer reviewed version of the following article: J. Malina, H. Kostrhunova, P. Scott, V. Brabec, Chem. Eur. J. 2021, 27, 11682. , which has been published in final form at http://doi.org/10.1002/chem.202101388. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited | ||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||
Date of first compliant deposit: | 27 April 2023 | ||||||
Date of first compliant Open Access: | 27 April 2023 | ||||||
RIOXX Funder/Project Grant: |
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