Divalent Naphthalene Diimide Ligands Display High Selectivity for the Human Telomeric G-quadruplex in K⁺ Buffer

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• G-quadruplex structures, particularly the human telomeric G-quadruplex (ht G4), are promising therapeutic targets for cancer treatment.
• Developing selective ligands for specific G-quadruplex forms is crucial for effective and safe anti-cancer therapies.
• Naphthalene diimide (NDI) derivatives are explored for their potential as G-quadruplex binders.

Purpose of the Study:

• To synthesize and characterize novel divalent cationic naphthalene diimide ligands.
• To evaluate the selectivity of these ligands towards the hybrid form of the human telomeric G-quadruplex (ht G4) in potassium buffer.
• To assess the anti-cancer activity and cytotoxicity of the most selective ligands.

Main Methods:

• Synthesis of novel naphthalene diimide ligands with varying cationic substituents.
• G-quadruplex binding assays to determine selectivity against various DNA structures (quadruplexes and duplexes).
• Cell viability assays using cancer cell lines (HeLa) and non-cancerous fibroblasts (WI-38).

Main Results:

• A series of divalent cationic naphthalene diimide ligands were synthesized.
• An imidazolium-bearing mannoside-conjugate ligand demonstrated unprecedented selectivity for the hybrid ht G4.
• A methylpiperazine-bearing ligand exhibited significant toxicity to HeLa cancer cells, exceeding doxorubicin, while showing lower toxicity to WI-38 cells.

Conclusions:

• Novel naphthalene diimide ligands can be designed for selective G-quadruplex targeting.
• The imidazolium-mannoside ligand represents a highly selective G-quadruplex binder.
• The methylpiperazine-NDI ligand shows potential as a selective anti-cancer agent with a favorable therapeutic window.