Chiral metallohelices enantioselectively target hybrid human telomeric G-quadruplex DNA

The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-c...

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Bibliographic Details
Published in:Nucleic acids research 2017-05, Vol.45 (9), p.5026-5035
Main Authors: Zhao, Andong, Howson, Suzanne E, Zhao, Chuanqi, Ren, Jinsong, Scott, Peter, Wang, Chunyu, Qu, Xiaogang
Format: Article
Language:English
Subjects:
Chemical Biology and Nucleic Acid Chemistry
Coordination Complexes - chemistry
DNA - chemistry
G-Quadruplexes
HeLa Cells
Humans
Iron - chemistry
Isomerism
Metals - chemistry
Telomerase - antagonists & inhibitors
Telomerase - metabolism
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Summary:The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx244