Cytotoxicity evaluation and DNA interaction of RuII-bipy complexes containing coumarin-based ligands

• Published in: Dalton transactions : an international journal of inorganic chemistry Vol. 50; no. 41; pp. 14908 - 14919
• Main Authors: Patrícia S V B de Almeida, Henrique Jefferson de Arruda, Gleyton Leonel S Sousa, Felipe Vitório Ribeiro, José Aleixo de Azevedo-França, Ferreira, Larissa A, Guedes, Guilherme P, Silva, Heveline, Kummerle, Arthur E, Neves, Amanda P
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 26.10.2021
• Subjects: Cancer; Coordination compounds; Coumarin; Crystal structure; Cytotoxicity; Fluorescence; Imidazole; Investigations; Ligands; Molecular docking; Oxygen atoms; Ruthenium compounds; Toxicity
• ISSN: 1477-9226; 1477-9234; 1477-9234
• DOI: 10.1039/d1dt01567b

Although there are various treatment options for cancer, this disease still has caused an increasing number of deaths, demanding more efficient, selective and less harmful drugs. Several classes of ruthenium compounds have been investigated as metallodrugs for cancer, mainly after the entry of imidazolH [trans-RuCl4-(DMSO-S)(imidazole)] (NAMI-A) and indazolH [trans-RuCl4-(Indazol)2] (KP1019) in clinical trials. In this sense, RuII complexes with general formula [Ru(L1–3)(bipy)2]PF6 (1–3) (L1 = ethyl 3-(6-methyl-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L2 = ethyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L3 = ethyl 3-(8-methoxy-2-oxo-2H-chromen-3-yl)-3-oxopropanoate and bipy = bipyridine) have been synthesized. The crystal structure of 2 revealed that the RuII atom lies on a distorted octahedral geometry with the deprotonated ligand (L2−) coordinated through β-ketoester group oxygen atoms. In vitro cytotoxic activity of the compounds was evaluated against 4T1 (murine mammary carcinoma) and B16-F10 (murine metastatic melanoma) tumor cells, and the non-tumor cell line BHK-21 (baby hamster kidney). Coordination with RuII resulted in expressive enhancement of cytotoxic activity. The precursors were inactive below 100 μM and the final RuII complexes (1–3) showed IC50 ranging from 2.0 to 12.8 μM; 2 being the most potent compound. DNA interaction studies revealed a greater capacity of the complexes to interact with DNA than the ligands, where, 2 exhibited the highest Kb constant of 2.2 × 104 M−1. Fluorescence investigation demonstrated that 1–3 are capable of quenching the fluorescence emission of the EtdBr–DNA complex up to 40%. Molecular docking showed that the interaction of 1–3 between the DNA base pairs from the coumarin portion was with scores of 67.28, 68.62 and 64.88, respectively, and 75.45 for ellipticine, suggesting an intercalative mode of binding. Our findings show that the RuII complexes are eligible for continuing to be investigated as potential antitumor compounds.