Pyridine Derivative of the Natural Alkaloid Berberine as Human Telomeric G₄-DNA Binder: A Solution and Solid-State...

Telomerase is an enzyme deputed to the maintenance of eukaryotic chromosomes; however, its overexpression is a recognized hallmark of many cancer forms. A viable route for the inhibition of telomerase in malignant cells is the stabilization of G-quadruplex structures (G₄) at the 3' overhang of telomeres. Berberine has shown in this regard valuable G₄ binding properties together with a significant anticancer activity and telomerase inhibition effects. Here, we focused on a berberine derivative featuring a pyridine containing side group at the 13th position. Such modification actually improves the binding toward telomeric G-quadruplexes and establishes a degree of selectivity in the interaction with different sequences. Moreover, the X-ray crystal structure obtained for the complex formed by the ligand and a bimolecular human telomeric quadruplex affords a better understanding of the 13-berberine derivatives behavior with telomeric G₄ and allows to draw useful insights for the future design of derivatives with remarkable anticancer properties.