Structure-activity Relationships of Substituted Ruthenium Azopyridine Complexes: A DFT and QSAR Study for Anticancer Applications

The anarchic proliferation of cells in all types of organs in the human body leads to tumours called cancer. Chemotherapy remains an alternative treatment. Transition metal-based agents such as cisplatin have been shown to be effective. However, their use is hampered by unwanted side effects. One alternative to platinum is ruthenium. Ruthenium azopyridine complexes are promising anticancer agents for the treatment of certain cancers by chemotherapy. The aim of this work is to design ruthenium azopyridine complexes with enhanced cytotoxic activity. These compounds are all derived from δ-Cl isomer of the ruthenium azopyridine complex RuCl2(Tazpy)2 by substituting toluene group of the Tazpy ligand with different benzene derivatives. The methyl substituent in toluene group is replaced by various substituents (-COCH3, -COOH, -CH2-COOH, -CH2-OH, -COH, -CONH2, -CNH2, CH3-O-, -CH2-CH3, OH-, -CH2-CH2-CH3 and -CH=CH2). A series of thirteen ruthenium complexes is studied using density functional theory (DFT) and time-dependent DFT (TD-DFT) at the B3LYP/Lanl2DZ level. Examination of the geometrical parameters of the compounds after optimization and frequency calculation indicates that all complexes have the same geometry whatever the nature of the substituent. This assumes an identical mode of interaction with the DNA base. The formation of compounds C4 and C7 is possible at temperatures above 298K. Also, the substituents -OH and -CH2-CH2-CH3 increase the chemical reactivity of the complex, while the binding and interaction affinity with DNA is amplified by the alkyl substituents (-CH2-CH3, -CH2-CH2-CH3) and -CH=CH2. The cytotoxic activity of the compounds against A498, H226, IGROV, MCF-7 and WIDR cancers is predicted using QSAR models. The substituents -CH2-COOH, -CH2-CH3, -CH2-CH2-CH3 and -CH=CH2 enhance the cytotoxicity of the ruthenium azopyridine complex. These compounds absorb in the visible range at wavelengths above 600nm. These metal ligand transitions are an advantage when it comes to using them in the photodynamic treatment of cancer or as a dye in dye-sensitized solar cells.