The interactions of Pu22 G-quadruplex, derived from promoter sequence, with antitumor acridine derivatives-An NMR/MD combined study.

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents that exhibit significant antitumor activity against a wide range of cancer cell lines and solid tumors . UAs consist of two different acridine-based ring systems, which are connected by an aminoalkyl linker. Recent studies have demonstrated that UAs can suppress the protooncogene, which is overexpressed in many tumor types. As a proposed molecular basis for this activity, UAs have been suggested to stabilize the G-quadruplex structure formed within the promoter region of . In this study, we performed spectroscopic and computational analyses to investigate the stereochemistry of the NHE III representative G-quadruplex, codenamed Pu22, in complex with two promising bisacridines, C-2045 and C-2053, as well as their monomeric counterparts, C-1311 and C-1748. C-1311 formed a well-defined 1:2 mol/mol DNA:ligand non-covalent adduct, whose solution structure was determined via 2D NMR. In contrast, C-1748 displayed weak and nonspecific interactions with the Pu22 G-quadruplex. Finally, the Pu22:UA complexes were examined using a combination of NMR and molecular modeling approaches, including umbrella sampling simulations. These results provide insights into the interaction mechanisms of UAs with G-quadruplex structures and highlight their potential as therapeutic agents targeting .