Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 21, Pages 8674-8683Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401119b
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Funding
- EPSRC through the White Rose Life Science DTC
- FCT [SFRH/BPD/27082/2006]
- QREN-FEDER through the Operational Program Competitiveness Factors-COMPETE
- National Funds through the FCT [PTDC/QUI-QUI/101022/2008]
- Fundação para a Ciência e a Tecnologia [PTDC/QUI-QUI/101022/2008] Funding Source: FCT
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We report DNA binding studies of the dinuclear ruthenium ligand [{Ru(phen)(2)}(2)tpphz](4+) in enantiomerically pure forms. As expected from previous studies of related complexes, both isomers bind with similar affinity to B-DNA and have enhanced luminescence. However, when tested against the G-quadruplex from human telomeres (which we show to form an antiparallel basket structure with a diagonal loop across one end), the Lambda Lambda isomer binds approximately 40 times more tightly than the Delta Delta, with a stronger luminescence. NMR studies show that the complex binds at both ends of the quadruplex. Modeling studies, based on experimentally derived restraints obtained for the closely related [{Ru(bipy)(2)}(2)tpphz](4+), show that the Lambda Lambda isomer fits neatly under the diagonal loop, whereas the Delta Delta isomer is unable to bind here and binds at the lateral loop end. Molecular dynamics simulations show that the Delta Delta isomer is prevented from binding under the diagonal loop by the rigidity of the loop. We thus present a novel enantioselective binding substrate for antiparallel basket G-quadruplexes, with features that make it a useful tool for quadruplex studies.
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