Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures.

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Telomeric DNA G-quadruplexes (G4) are crucial in cancer therapy.
• Naphthalene diimides (NDIs) are versatile chemical scaffolds.
• Targeting telomeres offers a strategy for cancer treatment.

Purpose of the Study:

• To synthesize and characterize novel naphthalene diimides (NDIs) with hybrid ligand-alkylating properties.
• To evaluate their binding affinity and selectivity towards telomeric G4 DNA.
• To assess their biological effects on cancer cells, specifically melanoma.

Main Methods:

• Synthesis of novel NDI-quinone methide (QM) conjugates.
• Fluorescence resonance energy transfer (FRET) and circular dichroism (CD) assays for DNA binding studies.
• In vitro alkylation assays on nucleosides and telomeric G4 DNA.
• Cell growth inhibition assays and analysis of telomere dysfunction and telomerase expression in melanoma cells.

Main Results:

• NDI-QMs demonstrated reversible binding and selective alkylation of telomeric G4 DNA.
• Stabilization of telomeric G4 DNA with a hybrid topology was observed.
• Selective reactivity towards telomeric G4 over single nucleosides was confirmed.
• A selected NDI significantly inhibited melanoma cell growth by inducing telomere dysfunction and down-regulating telomerase.

Conclusions:

• Hybrid ligand-alkylating NDIs represent a novel class of compounds with potential anticancer activity.
• These compounds selectively target telomeric G4 DNA, offering a mechanism for cancer therapy.
• The observed telomere dysfunction and telomerase down-regulation highlight their therapeutic potential in melanoma treatment.