New organoruthenium(II) complexes containing N, X-donor (X = O, S) heterocyclic chelators: Synthesis, spectral characterization, in vitro cytotoxicity and apoptosis investigation

Abstract

Four Schiff base ligands namely ((1E)-1-(1-(6-chloro-2-oxo-2H-chromen-3-yl) ethylidene)semicarbazide) (HL1), ((1E)-1-(1-(6-chloro-2-oxo-2H-chromen-3-yl)ethylidene thiosemicarbazide) (HL2), ((1E)-1-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene) semicarbazide) (HL3) and ((1E)-1-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene) thiosemicarbazide) (HL4) have been prepared, and the direct reaction of these ligands with [RuCl2(η6-p-cymene)]2 yielded the new cationic ruthenium(II) arene complexes (C I - C IV). The compounds were characterized using various spectroscopic methods. Spectroscopic analysis revealed that the ligands coordinated to ruthenium ion in a neutral bidentate fashion via N & S/O atoms. The in vitro anticancer activity of the ligands and complexes have been screened using MTT assay with two cancer cell lines, namely MCF-7 (human breast cancer cells) and A549 (human lung carcinoma). Interestingly, the cytotoxic nature of the complexes is much more potent than the standard drug cisplatin and their parent ligands with low IC50 values. The non-toxic nature of the compounds has been confirmed with human umbilical vein endothelial cells HUVEC cells. The morphological changes of the MCF-7 and A549 cells with the complexes C I- C IV have been studied by AO-EB (Acridine Orange-Ethidium Bromide) and Hoechst staining methods, and these results revealed that the complexes induced cell death only through apoptosis. The cytotoxic nature of the compounds was found to be C IV > C III > C II > C I > cisplatin > ligands. Complex C IV showed better activity due to the electron-donating hydroxyl group present in the 7th position of the coumarin ring. These results highlighted the strong possibility to develop highly active ruthenium arene complexes as anticancer agents.