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Specifically targeting mixed-type dimeric G-quadruplexes by berberine dimers


Three polyether-tethered berberine dimers (1a-c) have been studied on their binding affinity, selectivity and thermal stabilization towards human telomeric dimeric quadruplex DNA (G2T1). Compound 1a with the shortest polyether linker shows the highest affinity (Ka > 108 M-1) and 76-508-fold higher selectivity for mixed-type G2T1 over antiparallel G2T1 and three monomeric G-quadruplexes, including human telomeric monomeric quadruplex G1, c-kit 1 and c-kit 2. Compound 1a induces the formation of quadruplex structures and shows higher thermal stabilization for mixed-type G2T1 than for antiparallel G2T1, G1 and ds DNA. Spectroscopic studies suggest that compound 1a might bind mixed-type G2T1 via end-stacking and external binding modes. These results suggest that the polyether linkers in these compounds play an important role in regulating the binding affinity and selectivity towards mixed-type G2T1, and that compound 1a could target mixed-type G2T1 on other genome regions with antiparallel G2T1 and monomeric G-quadruplexes. These results may provide useful guidance for the rational design of selective multimeric G-quadruplex binders and potential anticancer agents.

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Publication details

The article was received on 18 Sep 2017, accepted on 14 Nov 2017 and first published on 14 Nov 2017

Article type: Paper
DOI: 10.1039/C7OB02326J
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
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    Specifically targeting mixed-type dimeric G-quadruplexes by berberine dimers

    Z. Li, T. Liao, C. Dong, J. Yang, X. Chen, L. Liu, Y. Luo, Y. Liang, W. Chen and C. Zhou, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB02326J

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