Synthesis, structures, and DNA and protein binding of ruthenium(ii)-p-cymene complexes of substituted pyridylimidazo[1,5-a]pyridine: enhanced cytotoxicity of complexes of ligands appended with a carbazole moiety

Abstract

A series of organometallic Ru(II)-arene complexes of the type [(η⁶-p-cymene)Ru(L)Cl](BF₄) 1–6, where L is 3-phenyl-1-pyridin-2-yl-imidazo[1,5-a]pyridine (L1), dimethyl-[4-(1-pyridin-2-yl-imidazo[1,5-a]pyridin-3-yl)phenyl]-amine (L2), diphenyl-[4-(1-pyridin-2-yl-imidazo[1,5-a]pyridin-3-yl)phenyl]amine (L3), 9-[4-(1-pyridin-2-yl-imidazo-[1,5-a]pyridin-3-yl)-phenyl]-9H-carbazole (L4), 9-ethyl-3-(1-pyridin-2-yl-imidazo-[1,5-a]pyridin-3-yl)-9H-carbazole (L5), and 10-ethyl-3-(1-pyridin-2-yl-imidazo[1,5-a]pyridin-3-yl)-10H-phenothiazine (L6), has been isolated and characterised by elemental analysis, ESI-MS, NMR and cyclic voltammetry. The photophysical properties of the complexes have been studied by electronic absorption and emission spectral techniques. All the ligands exhibit tuneable photoluminescence behaviour with the emission maximum spanning through the visible region (475–670 nm) in dichloromethane while all the complexes are emissive in acetonitrile. The single crystal X-ray structures of 2, 3 and 4 reveal that the complexes have a “piano stool” coordination geometry, comprising one π-bonded arene centroid, two σ-bonded nitrogen atoms from the chelating ligand and one Cl⁻ ion. From DNA induced EthBr emission quenching experiments the apparent DNA binding constants of the complexes (K_app) have been evaluated, which follows the order, 2 (1.3) < 1 (1.5) < 6 (1.7) < 4 (1.8) < 5 (2.4) < 3 (2.8 × 10⁵ M⁻¹). This trend reveals the role of ligand hydrophobicity on the DNA binding ability of complexes, the non-planar phenothiazine ring (6) and the specific interactions the planar carbazole chromophore (4, 5) make with DNA. The value of K_sv obtained as the slope of the linear plot of F₀/F vs. [complex] follows the order 1 (3.1) < 6 (8.2) < 2 (13.1) < 3 (15.7) < 5 (17.1) ≈ 4 (17.2 L M⁻¹), which supports the inferences from DNA binding experiments. All the complexes, except, 1 and 2 (>100 μM), exhibit in vitro cytotoxicity against A549 small lung cancer cell lines higher than cisplatin (∼69 μM), as revealed by both MTT (11.8–18.1 μM) and crystal violet staining (12.7–23.5 μM) assays, which is in agreement with their DNA and BSA binding affinity. Also, the complexes 3–6 cause higher cell death mainly through the apoptotic mode, as revealed by the observation of a higher percentage of apoptotic cells in AO/EB (36–43%) and Annexin V-Cy3 (36–45%) stained cancer cells.