Synthesis and Molecular Modeling of Thermally Stable DNA G-Quadruplexes with Anthraquinone Insertions

Two new phosphoramidite building blocks for DNA synthesis were synthesized from 1,5- and 2,6-dihydroxyanthraquinones through alkylation with 3-bromo-1-propanol followed by DMT-protection. The novel synthesized 1,5- and 2,6-disubstituted anthraquinone monomers H-15 and H-26 are incorporated into a G-quadruplex by single and double replacements of TGT and TT loops. Monomers H-15 and H-26 were found to destabilize G-quadruplex structures for all single replacements of TGT or TT loops. The largest destabilization was observed when H-26 linker replaced a TT loop. In contrast, the presence of anthra-quinone monomers in two TT loops led to 1-18 degrees C increase in their thermal stabilities, depending on linker attachment geometry of the monomers. The presence of H-15 and H-26 linkers replacing two TT loops results in the highest stabilization of the G-quadruplex structure by 18.2 degrees C. Circular dichroism spectroscopy of all anthraquinone-modified quadruplexes revealed no change of the antiparallel structure when compared with the wild type under potassium buffer conditions. The significantly increased thermostabilities were interpreted by molecular modeling of anthraquinone-modified G-quadruplexes.