Metal-Organic Compounds as Anticancer Agents: Versatile Building Blocks for Selective Action on G-quadruplexes

Since the 1980s, cancer research has focused primarily on developing new therapeutic agents targeting DNA alterations rather than understanding cancer as an integrated system composed of several modules. In this sense, G-quadruplex (G4) nucleic acids are a promising target for drug development for cancer therapy since they exist in the chromosomal telomeric sequences and the promoter regions of numerous genes. The G4 structures within telomeric DNA can inhibit telomerase activity and prevent the proliferation and immortalization of cancer cells. Furthermore, such G4 systems within the promoter regions of oncogenes can inhibit the transcription and expression of the oncogene.

The rational design of small molecules such as organic ligands and their metal- organic derivative compounds can stabilize G4 structures through different binding modes on several G4 DNA topologies. Metal-based compounds have demonstrated their competitiveness compared to organic molecules to distinguish G4 over the DNA duplex owing to their convenient coordination features, positive charge, and electron density promoted by organic ligand.

This article is a comprehensive review of metal compounds G4-binders and their structural features that confer them the ability to recognize G-quartets and stabilize several DNA G4s.

This stabilization can be achieved through extended square aromatic surfaces, increased hydrophobicity, different auxiliary ligands, axially coordinated ligands, and the nature of the metal center.