Xiaogang Qu

DNA Loop Sequence as the Determinant for Chiral Supramolecular Compound G-Quadruplex Selectivity

It is important to develop G-quadruplex binding agents that can discriminate between different quadruplexes. Recently we reported the first example that a chiral supramolecular complex can selectively stabilize human telomeric G-quadruplex among different G-quadruplex and duplex DNA, and the two enantiomers show different inhibition effect on telomerase activity. Here, we report that DNA loop sequence can be determinant for this chiral complex G-quadruplex selectivity. Adenine in the diagonal loop plays an important role in G-quadruplex hybrid structural transition, thus, it strongly influences the chiral complex induced DNA structural transition. The complexs preference for human telomeric DNA and its chiral selectivity prompted us to investigate whether the two enantiomers, M and P, can show different effects on cancer cells. The P enantiomers chiral selectivity has been demonstrated in cancer cells by telomere shortening, beta-galactosidase activity, and up-regulation of cyclin-dependent kinase inhibitors p16 and p21.

Analysis of drug-DNA binding data.

Publisher Summary This chapter discusses the analysis of drug-DNA binding data. This chapter describes the protocols for the numerical analysis of primary fluorescence and absorbance titration data that have evolved during the past decade. The rational design of new DNA binding agents requires a thorough understanding of the thermodynamics of the DNA binding of the existing drugs. Fundamental to any thermodynamic characterization of the drug–DNA interactions is the determination of binding constants. Because many DNA binding drugs exhibit large changes in absorbance or fluorescence on binding, these changes are commonly used to determine the distribution of free and bound drug in solution to construct binding isotherms that may be used to obtain binding constants. Fluorescence and absorbance spectroscopies provide a powerful means of determining drug–DNA binding constants. In addition, the chapter also describes the application of nonlinear least squares fitting methods, coupled with Monte Carlo analysis, to reliably estimate limiting optical parameters and their errors that are necessary to compute the distribution of free and bound ligand from spectroscopic data.

Hydration of drug-DNA complexes: greater water uptake for adriamycin compared to daunomycin.

Water is an integral part of DNA, and the conserved water molecules at the binding sites can modulate drug binding to DNA or protein. We report here that anthracycline antitumor antibiotics, adriamycin (AM) and daunomycin (DM), binding to DNA is accompanied by different hydration changes, with AM binding resulting in the uptake of about twice as many water molecules as DM. These results indicate that water is playing an important role in drug binding to DNA.