Ruthenium(II)-arene complexes with naphthalimide-tagged N,O- and N,N-chelating ligands: Synthesis and biological evaluation

•Synthesis of new ruthenium(II)-arene complexes using naphthalimide-tagged N,O- and N,N-based chelating ligands.•Cytotoxic activity against cancerous and normal cell lines.•DNA-binding studies.•Influence of the naphthalimide chromophore and intercalating agent on cytotoxicity and DNA-binding.•Influence of chain length and substituents on cytotoxicity and DNA-binding.

A new family of ruthenium(II)-arene complexes with naphthalimide functionalized N,O- and N,N-chelating ligands of the general formula [Ru(η6-p-cymene)Cl(L)] (2b–4b) (where: L = 4-[N-(2-((2-hydroxy-5-Br-phenyl)methyl imino)ethyl)]-N-butyl-1,8-naphthalimide (2a), 4-[N-(2-((2-hydroxy-5-Cl-phenyl)methyl imino)ethyl)]-N-butyl-1,8-naphthalimide (3a), and N-butyl-4-[N-(2-((2-hydroxy-5-NO2-phenyl)methylimino)ethyl)]-N-butyl-1,8-naphthalimide (4a), and [Ru(η6-p-cymene) Cl(L′)]Cl (8b–9b) (where L′ = N-(2,2′-dipyridylaminoethyl)-1,8-naphthalimide (8a) and N-(2,2′-dipyridylaminopropyl)-1,8-naphthalimide (9a) have been synthesized and characterized. The in vitro cytotoxic activities of the ligands (2a, 9a) and the complexes (2b–4b, and 8b–9b) have been evaluated against the human melanoma skin cancer (CRL7687) and normal noncancerous (CA-M75) cell lines. All the compounds exhibit potent cytotoxic activities with IC50 values of ∼1 μM or less but displayed variable selectivity. The compounds with N,O-ligands were found to be less selective than those containing N,N-chelating ligands. Notably, complex 9b displayed the highest selectivity towards cancer cells over health cells. The interactions of the compounds with calf thymus DNA (CT-DNA) have also been investigated by UV–Vis and fluorescence spectra, ethidium bromide displacement assay and gel electrophoretic studies, which revealed that the compounds bind to CT-DNA moderately presumably through an intercalative mode.

Graphical abstractTwo series of neutral and cationic ruthenium(II)-arene complexes containing naphthalimide-conjugated chelating ligands were synthesized. The new complexes were characterized by NMR, UV–Vis spectroscopy, and ESI mass spectrometry. The in vitro cytotoxic activity of the new complexes was determined by MTT assay.Figure optionsDownload full-size imageDownload as PowerPoint slide