Computational studies, synthesis and characterization of Ruthenium(ii) anticancer complexes.

Abstract

As demand for water grows in South Africa, alternative sources are actively being sought to augment conventional water supply. While domestic rainwater harvesting has been put forward as one such an alternative water supply, little information is available on whether harvested rainwater is safe for human use or even how local communities feel about using the water from such an alternative source. The SU team tested the chemical and microbial quality of rainwater collected from the rainwater tanks of 29 houses over six months. In addition, 68 households were interviewed to investigate the acceptance and perception on the use of the domestic rainwater harvesting tanks. The results obtained for the chemical analysis indicated that the rainwater quality was within potable, chemical standards. Metals, cations and anions that were analysed for in the harvested rainwater samples were all below the recommended drinking water guidelines. However, the microbial analysis showed that the presence of the following group of indicator organisms exceeded the recommended drinking water guidelines: total coliforms, Eneterocci, faecal coliforms, and heterotrophic bacteria. The presence of several opportunistic pathogens, including E.coli, Cryptosporidium and Salmonella, were also detected. In short, the water from the rainwater harvesting tanks in Kleinmond is not fit for human consumption, and prior treatment is required before the water source can be used for drinking purposes. The main causes of contamination are dirt and faeces (from birds and small animals) on the roof surface, which fall into the tank. Other sources of rainwater contamination include leaf debris and organic material washed into the tank, animals or birds that fall into uncovered tanks as well as breeding mosquitoes. It was found that many of the households placed their garbage bags on top of the tanks to protect them from being ripped open by stray dogs. These garbage bags could easily contaminate the rainwater, especially if the tanks are leaking or broken and/or the lid is absent. This general lack of awareness of contamination hazards highlights the importance of training users in the proper use and maintenance of the technology. It has been recommended that some form of pre-treatment be installed to make the rainwater safe for drinking. As a follow up to this part of the project, the SU team is now investigating the use of solar water pasteurisation and filtration systems for the treatment of harvested rainwater. Interestingly, the SU user survey indicated that the majority of community members of the Kleinmond Housing Scheme instinctively steered clear of using the water from their rainwater harvesting tanks for drinking purposes. About two-thirds of the respondents do not use the water in the tank for drinking, while by far the majority of those who use it for drinking do so only sometimes (24%). The majority of respondents who do drink the water pre-treat it first. One mother reported that her baby developed a rash after rainwater was used to bath him, while others said that drinking the water was ‘bad for your stomach’. The majority of respondents indicated that they use the harvested rainwater for household chores instead, such as laundry, cleaning, and gardening. One respondent was even applying his rainwater to help run his small car wash business. This thesis is centred on the application of Ru-based complexes as a promising alternative to cis-platin in cancer chemotherapy. Cis-platin is known to be the most prescribed chemotherapy which has more than 70% application in cancer cases especially the testicular cancer. An insight is provided in Chapter One and Two into the literatures reports on the application of Ru(II)-based complexes in cancer chemotherapy. In order to address some of the pressing challenges in rational design of Ru-based anticancer complexes, section 3.3 and 3.4 deal with efforts to elucidate the complication of their chemistry and instability while in section 3.5 efforts are made to find solution to the lack of proper knowledge of their targets using different theoretical approaches as presented in Chapter Three. In addition to the theoretical study, this thesis also comprises of the synthesis of the bis-pyrazole derivatives type of ligands and the derivatives of their Ru(II)-based complexes as provided in Chapter Four and Five respectively. Also the computational methods were used to elucidate the structural and spectroscopic properties of the synthesised ligands and their Ru(II)-based complexes. The geometrical and electronic properties are studied in relation to the stability and the reported anticancer activities of Ru(II)-based complexes in section 3.3. In subsection 3.3.1, several quantum properties including the natural energy decomposition analysis (NEDA) and quantum theory of atoms in a molecule (QTAIM) are computed on three models of RAPTA-C complexes using DFT with hybrid functional and basis set with ECP and without ECP. The higher stability of Carbo-RAPTA-C and Oxalo-RAPTA-C over RAPTA-C comes from the lower exchange repulsion and higher polarization contributions to their stability which gives insight into experimental observation. A similar study was carried out in subsection 3.3.2 on half-sandwich Ru(II)-based anticancer complexes with 6-toluene and 6-trifluorotoluene. The trifluorotoluene and the hydrated models are characterised with higher charge transfer, polarizability, synergistic effect of ligand fragments, stronger and higher HB interactions that support their reported experimental anticancer activities and the mechanism of their activation by hydrolysis. Also in the subsection 3.3.3, the factors that determine the stability and the effects of non-covalent interaction on the two models of these half-sandwich 6-arene ruthenium anticancer complexes and their respective hydrated forms were investigated using DFT method. Lastly in section 3.3, the subsection 3.3.4 deals with the intramolecular properties of five sets of ruthenium based anticancer complexes using DFT method. The spectroscopic and the non-linear optical properties of selected Ru(II) anticancer complexes are shown in Section 3.4. In subsection 3.2.1, DFT method was applied to study the thermodynamic and spectroscopic properties of three Ru-based complexes in order to give possible reasons for the reported experimental stability of complexes 1 and 2 with bidentate chelating ligands than complex 3. A further study was carried out in Subsection 3.4.2 where computational method was used to gain insight into the correlation between the chemistry of the hydrolysis and the anticancer activities of selected Ru(II)-based complexes. Lastly in this section, subsection 3.2.3 deals with application of different density functional methods (DFT) to optimize and study the chemistry of five potential anticancer complexes in terms of their electronic, conductive and spectroscopic properties. The carboxylic and pyrazole units are found to significantly enhance the polarizabilities and hyperpolarizabilities of the complexes while the chloride only improves the polarity of the complexes. The possible targets of Ru(II)-based anticancer complexes are predicted using docking methods as presented in section 3.5 of this thesis. In subsection 3.5.1, the interactions of selected Ru(II)-based complexes with different cancer receptors are carried out using computational docking. The study focuses more on finding alternative protein targets other DNA for some Ru(II)-based complexes using computational docking. A further study on addressing the problem of the improper knowledge of of the targets of Ru-based anticancer complexes was carried out in subsection 3.5.2. Some promising anticancer complexes of Ru(II) such as RAPTA based complexes formulated as [Ru(η6-p-cymene)L2(pta)] and those with unusual ligands are docked against receptors using Autodock, Glide and Gold. Lastly in section 3.5, docking packages Molegro and Autodock were applied in subsection 3.5.3 to predict the anticancer activities of selected Ru(II) complexes against twelve anticancer targets. Introducing the quantum calculated atomic charges of the optimized geometries is found to significantly improve the docking predictions of these anticancer metallocompounds. In section 4.3-4.6, the spectroscopic and the geometric properties of ligands with pyrazole, methylpyrazole, bipyridine and phenanthroline derivatives were studied at both experimental and computational levels. The computational results are perfectly in agreement with the experimental results especially in terms of the spectroscopic properties. The spectroscopic analyses as well as the computed properties were used to establish the successful synthesis of the ligands. Many of the functional groups in these ligands are found to be Raman active which also help in their spectroscopic elucidation. Lastly in chapter five, the method used for the synthesis of forty Ru(II)-based complexes were presented with their experimental spectroscopic features being elucidated using theoretical methods. A very high correlation was observed between experimental and theoretical characterisation of the complexes which is an indication of successful synthesis of the complexes.