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

J Med Chem. 2025 Jan 1. doi: 10.1021/acs.jmedchem.4c01665. Online ahead of print.

Abstract

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.