The influence of N-methylphenethylamine moiety on the antibacterial and anticancer activity in vitro of the phosphino Ir(III) and Ru(II) organometallic compounds

The phosphine derivative of the alkaloid, specifically the N-methylphenethylamine (Ph2PCH2N(CH3)(CH2)2Ph, NMPEA) and the half-sandwich Ir(III) (Ir(η5-Cp*)Cl2Ph2PCH2N(CH3)(CH2)2Ph, IrPNMPEA) and Ru(II) (Ru(η6-p-cymene)Cl2Ph2PCH2N(CH3)(CH2)2Ph, RuPNMPEA) coordination compounds with this ligand were synthesised. Subsequently, for their characterisation, several physicochemical methods, such as 1D and 2D NMR, ESI(+)MS, electronic absorption and emission spectroscopy (UV-Vis range), cyclic voltammetry, elemental analysis, and thermogravimetry were applied. In addition, the molecular structures of the obtained compounds were optimised at the density functional theory level. Moreover, their preliminary antibacterial activity in vitro towards various Gram-positive and Gram-negative bacteria strains was investigated in comparison to the compounds without the alkaloid motif (Ir(η5-Cp*)Cl2Ph2PCH2OH, IrPOH and Ru(η6-p-cymene)Cl2Ph2PCH2OH, RuPOH), that were synthesised based on the literature reports. It was proved that the addition of the N-methylphenethylamine moiety into the organometallic Ir(III) and Ru(II) compounds not only increased their antibacterial activity in vitro, but also selectivity towards Gram-positive bacteria, for instance Bacillus subtilis and Staphylococcus aureus. Interestingly, IrPNMPEA was more bactericidal than RuPNMPEA. Subsequently, the preliminary anticancer activity in vitro based on the MTT assay revealed that the alkaloid motif incorporation significantly improved the overall selectivity of examined complexes towards selected cancer cell lines. The IrPNMPEA and RuPNMPEA exhibited significant cytotoxicity towards the human breast adenocarcinoma (MCF-7) cell line and simultaneously lack cytotoxicity against a normal cell lines, in contrast to the IrPOH and RuPOH. Additionally, the intracellular mechanism of anticancer activity in vitro of the IrPOH and RuPOH was investigated. It indicated that IrPOH can accumulate in several cancer cells, decrease the mitochondrial membrane potential, activate the caspase-9 and -3, generate the reactive oxygen species and lipid peroxides, as well as induce the apoptotic pathway of cancer cell death considerably better than RuPOH. Moreover, it was important to understand the potential mode of action of examined coordination compounds, related to their interactions with several biomolecules, which are present in both prokaryotic and eukaryotic cells. Stability studies in solution and electrostatic properties calculations for the IrPNMPEA and RuPNMPEA revealed that in some conditions Cl- ligands can be exchanged into water molecules. Consequently, these complexes can covalently interact with various biomolecules, like deoxyribonucleic acid (DNA), β-nicotinamide adenine dinucleotide (NADH), ascorbic acid (Asc), and glutathione (GSH). It was demonstrated that IrPOH and RuPOH display multimodal interactions with DNA, but intercalation and minor groove binding were the dominant ones.Similar results were obtained for the RuPNMPEA. Whereas, IrPNMPEA prefers to intercalate between the nitrogen base pairs of the DNA. Additionally, IrPNMPEA caused the double-strand decomposition of the DNA plasmid pBR322, in contrast to the IrPOH, RuPOH, and RuPNMPEA that led to the single-strand plasmid cleavage. Moreover, it was proved that IrPNMPEA and RuPNMPEA accelerate the oxidation of NADH, Asc and GSH. However, the formation of various adducts with these biomolecules by IrPNMPEA, can indicate its higher antibacterial activity in vitro. Furthermore, the synthesis of novel phosphine-alkaloid ligand complexes, detailed physicochemical characteristic, as well as preliminary anticancer activity in vitro, along with the IrPNMPEA and RuPNMPEA, were described in this doctoral dissertation as a perspective.