Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G quadruplexes

Abstract

In this work, the interaction of six natural benzo[c]phenanthridine alkaloids (macarpine, sanguilutine, sanguirubine, chelerythrine, sanguinarine and chelirubine) with parallel and antiparallel G-quadruplex DNA structures was studied. HT22 corresponding to the end of human telomere and the modified promoter oncogenes c-kit21 and Pu22 sequences have been used. Spectroscopically-monitored melting experiments and fluorescence titrations, competitive dialysis and nuclear magnetic resonance spectroscopy were used with this purpose. The results showed that these alkaloids stabilized G-quadruplex structures in terms of increments of Tm values (from 15 to 25 oC) with high selectivity over duplexes and unfolded DNA. The mode of binding was mainly by stacking on the terminal G-tetrads with stoichiometries 1:2 (DNA:ligand). The presence of non-specific electrostatics interaction was also observed. Overall, the results pointed to a strong stabilization of G-quadruplex structures by these alkaloids.