Selective Delivery of Anticancer Natural G‑Quadruplex Ligands by the AT11 Aptamer for Gastric Cancer Treatment

Searching for G-quadruplex-selective ligands as anticancer agents, we recently identified the natural compounds bulbocapnine, chelidonine, dicentrine, ibogaine, and rotenone as novel interactors of G-quadruplexes. Herein, to investigate their ability to interact with a specific carrier for selective delivery to cancer cells, the dimeric G-quadruplex-forming aptamer AT11 was used as a model. NMR spectroscopy, molecular modeling, circular dichroism, and fluorescence spectroscopy allowed the preferential interaction to be proven with the 3′-end G-quartet for bulbocapnine, chelidonine, dicentrine, and ibogaine, whereas with the 5′-end G-quartet region for rotenone. The anticancer activity of the AT11/natural compounds complexes was evaluated on gastric cancer cells using the free aptamer and free natural compounds as controls. Notably, all complexes caused a significant decrease in cancer cell viability, also producing synergistic effects. Remarkably, no relevant effects were detected on noncancerous cells, denoting the importance of delivering the natural compounds by AT11 G-quadruplex to obtain selective antiproliferative effects on cancer vs. normal cells.