We have synthesized a series of bifunctional thymine recognition agents consisting of a Zn(II) cyclen macrocyclic motif and an aromatic pendent group which selectively binds thymines in the lateral loops of G-quadruplexes. The binding of these bifunctional complexes to various G-quadruplexes was characterized using isothermal titration calorimetry, circular dichroism and fluorescence spectroscopy. In addition, a PCR stop assay was utilized to determine if these compounds inhibit Taq polymerase by stabilizing the G-quadruplex. From these studies a Zn(II) cyclen with a bound dansyl pendent group, Zn(DSC), exhibited selective binding to the H-Telo G-quadruplex with a Kd of 2.5 µM and a binding stoichiometry of 2:1. The PCR stop assay for H-Telo shows Zn(DSC) inhibits Taq polymerase with an IC50 of 3.0 ± 1 µM. The overall results from this study shows that these bifunctional complexes can selectively bind and stabilize G-quadruplexes making them potential therapeutic agents.

Selective binding of bifunctional Zn(II) complexes to G-quadruplex DNA

249th National Meeting (2015)

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