Diphenylaminothiophen-derived fluorescent ligands targeting mitochondrial DNA G-quadruplexes potentially for triple-negative breast cancer therapy

Mitochondrial DNA G-quadruplexes (mtG4s) are thought to play crucial roles in Mitochondrial Metabolism and may also represent a potential target for Anticancer drugs. However, mtG4s remain understudied, necessitating the development of more promising fluorescent ligands specifically targeted to them. In this study, we designed and synthesized a targeted library of diphenylaminothiophen (DPAT)-derived compounds, and subsequently evaluated their optical properties and binding affinities towards mtG4s. From this library, we identified SF3 as the most promising ligand for further investigation. Our findings revealed that SF3 was an exceptional mtG4-targeted near-infrared (NIR) fluorescent ligand, of which the fluorescence could be switched on through the G4-mediated disassembly of its H-aggregates into monomers with restricted conformation, featuring DBIE mechanism. Notably, SF3 significantly inhibited the transcription and replication of mtDNA, disrupted Mitochondrial Metabolism, induced cell cycle arrest, triggered Apoptosis, and demonstrated robust Anticancer activity against triple-negative breast Cancer (TNBC) either in vitro or in vivo. Collectively, SF3 can serve as a practical chemical tool for investigating mtG4s and holds potential for further development into an innovative Anticancer agent.

Diphenylaminothiophen; Fluorescent ligand; Mitochondrial G-quadruplex.