Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents

Iron homeostasis is strictly related to numerous physiological
pathways including cell cycle progression and cell growth. The newest
anticancer strategies focus on either depleting the cells with a suitable
chelator or increasing their loading by administering iron complexes
to induce ferroptosis. Iron depletion inhibits cell proliferation,
while iron overload induces the damage of guanine nucleobases in G-quadruplex
structures via ROS generation, leading to genome instability. Here,
we demonstrated that designing a molecular chimera embodying structural
requirements for both iron chelation and G-quadruplex binding can
result in dual-targeting compounds endowed with synergistic anticancer
effects. We designed, synthesized, and tested a library of such compounds
through biophysical and biological experiments. Compound 16 emerged as a lead candidate and a pharmacological tool able to chelate
iron and stabilize G-quadruplexes in human leukemia Jurkat cells.
Notably, it also localizes in the cell nucleus, serving as an intrinsically
fluorescent nuclear tracer for the labile iron pool.