ADVANCES IN G-QUADRUPLEX CHEMISTRY: FROM MOLECULAR INSIGHTS TO MEDICINAL APPLICATIONS

Priya A.*, Mahesh Kumar N., Dr. Shachindra L. Nargund

G-quadruplexes (G4s) are guanine-rich DNA and RNA structures stabilized by stacked guanine tetrads and metal cations. Once considered structural curiosities, they are now recognized as dynamic regulators of telomere function, oncogene transcription, and repeat-associated toxicity. Their structural diversity-spanning parallel, antiparallel, and hybrid conformations, has driven intense interest in ligand design. Medicinal chemistry has yielded diverse scaffolds such as acridines, carbazoles, naphthalene diimides, and natural macrocycles like telomestatin, each exploiting π–π stacking or groove interactions to stabilize specific G4 topologies. Importantly, several compounds have advanced beyond preclinical testing: quarfloxin (CX-3543) entered Phase II trials for neuroendocrine tumours, and CX-5461, initially described as a polymerase I inhibitor, is now recognized to act through G4 stabilization and is under clinical evaluation in haematological cancers. Together, these examples illustrate that G4-targeting chemistry is moving from concept to clinic. Beyond oncology, opportunities are emerging in neurodegenerative disease, viral infection, and cardiovascular disorders, underscoring the therapeutic versatility of these structures. Continued progress in structure-guided design and drug-like optimization will be key to realizing the full medicinal potential of G-quadruplex ligands. This review captures recent advances in Gquadruplex chemistry, spanning structural insights, ligand discovery, and translational applications, while highlighting future directions for their integration into mainstream drug discovery.