Side-Chain-Dependent Binding of bis-Naphthalimide Self-Assembled Nanoparticles to G‑Quadruplex DNA for Potential Anticancer Therapy

Novel bis-naphthalimide (NI)-based molecules composed of space linkers of phenyl dialkyne (bis-NI1 and bis-NI2), triazole (bis-NI3 and bis-NI4), and alkyne (bis-NI5 and bis-NI6) with the distinctive side chain of 2,6-diisopropylaniline or 2,4,6-trimethylaniline were designed and synthesized as nanoparticles (NPs) that bind to G-quadruplex (G4) DNA. The supramolecular assemblies of the bis-NIs were found to form isolated spheres (bis-NI1, bis-NI3), dumbbells with or without a cylindrical bridge (bis-NI2, bis-NI4), and needle-like structures (bis-NI6). The side chain of 2,4,6-trimethylaniline is suggested to play a key role in the self-assembly of the bridge-connected shape such as dumbbells or needle in bis-NIs with three different space linkers. The small sphere shaped NP formed by bis-NI1 displayed both intercalation and groove binding to G4-DNAs, while a larger sphere shaped NP of bis-NI3 represented binding to the G4-DNA groove. The dumbbells of bis-NI2 showed both intercalation and groove binding to G4-DNAs, whereas the dumbbells of bis-NI4 represented binding to the G4-DNA groove. The needle-shaped bis-NI6 exhibited both intercalation and groove binding to G4-DNAs. Different morphologies of self-assembled bis-NIs provided different IC50 values. Furthermore, bis-NI1, bis-NI4, and bis-NI6 induced cell cycle arrest (G1/S phase) and apoptosis in cancer cells. This suggests bis-NI1, bis-NI4, and bis-NI6 are potential anticancer agents.