The research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of... Show moreThe research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of platinum and palladium compounds utilizing the [Pt(bapbpy)]2+ scaffold. The study identifies intercalation as the primary mechanism of action for these complexes. Furthermore, it provides a detailed structure-activity relationship analysis, highlighting the critical role of the complex's protonation state in influencing its biological activity and efficacy. Subsequently, the study delves into photoactivated chemotherapy (PACT) using ruthenium (II) complexes, where light activation of ruthenium complexes enables targeted drug delivery to tumor cells, thereby reducing adverse effects. This research emphasizes the development of ruthenium-based compounds that can photorelease a DNA repair inhibitor, specifically targeting the RAD51 protein, essential for Homologous Recombination (HR). By disrupting the DNA repair mechanisms in cancer cells, this approach seeks to enhance the cytotoxicity of the therapy and address drug resistance. Show less
Producing green energy has become the main goal in our society in the search of reducing or eliminating the carbon emission from fossil fuels. In this project, proteins were used as a tool to... Show moreProducing green energy has become the main goal in our society in the search of reducing or eliminating the carbon emission from fossil fuels. In this project, proteins were used as a tool to develop an artificial system capable of promoting the most demanding reaction in photosynthesis, water oxidation, as a new concept of producing energy from a green source. For this purpose, a screening study of the interaction between selected proteins and a library photocatalytic ruthenium and cobalt complexes was carried out. The results from such study allowed the production of two types of artificial metalloenzymes (ArM) which were proven to be able to perform water oxidation reaction via blue light irradiation. As well, an unusual interaction between proteins which promote the photocatalytic O2 evolution from water. These findings lead to develop ruthenium and cobalt metalloenzymes as promising candidates for artificial photosynthesis in bio-inspired systems Show less
The biological application of photoactivatable ruthenium anticancer prodrugs is limited by the need to use poorly penetrating high-energy visible light for their activation. Upconverting... Show moreThe biological application of photoactivatable ruthenium anticancer prodrugs is limited by the need to use poorly penetrating high-energy visible light for their activation. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, can solve this issue, provided that they form stable, water (H2O)-dispersible nano-conjugates with the prodrug and that there is efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the ruthenium(II) polypyridyl complex [Ru(bpy)(2)(3(H))](PF6)(2) ([1](PF6)(2)), where bpy = 2,2-bipyridine and 3(H) is a photocleavable bis(thioether) ligand modified with two phosphonate moieties. This ligand was coordinated to the ruthenium center through its thioether groups and could be dissociated under blue-light irradiation. Complex [1](PF6)(2) was bound to the surface of NaYF4:Yb3+,Tm3+@ NaYF4:Nd3+@NaYF4 core-shell-shell (CSS-)UCNPs through its bis(phosphonate) group, thereby creating a H2O-dispersible, thermally stable nanoconjugate (CSS-UCNP@[1]). Conjugation to the nanoparticle surface was found to be most efficient in neutral to slightly basic conditions, resulting in up to 2.4 x 10(3) Ru-II ions per UCNP. The incorporation of a neodymium-doped shell layer allowed for the generation of blue light using low-energy, deep-penetrating light (796 nm). This wavelength prevents the undesired heating seen with conventional UCNPs activated at 980 nm. Irradiation of CSS-UCNP@[1] with NIR light led to activation of the ruthenium complex [1](PF6)(2). Although only one of the two thioether groups was dissociated under irradiation at 50 W.cm(-2), we provide the first demonstration of the photoactivation of a ruthenium thioether complex using 796 nm irradiation of a H2O-dispersible nanoconjugate. Show less
Metal-based prodrugs based on ruthenium(II) polypyridyl complexes have proven to be very suitable for application in both photodynamic therapy (PDT) and photo-activated chemotherapy (PACT). As most... Show moreMetal-based prodrugs based on ruthenium(II) polypyridyl complexes have proven to be very suitable for application in both photodynamic therapy (PDT) and photo-activated chemotherapy (PACT). As most of these complexes unfortunately require poorly-penetrative, potentially-toxic blue light for their photo-activation, a lot of research effort has been dedicated to the development of prodrug systems that can be activated using near-infrared light, which is less harmful and penetrates deeper into human tissue. Thulium-doped upconverting nanoparticles (UCNPs) produce the desired blue light upon excitation with near-infrared light, allowing for the development of a drug delivery system in which ruthenium prodrugs are activated with near-infrared light. This thesis deals with the development of several new photo-activatable ruthenium polypyridyl complexes and the investigation of their photochemistry. Furthermore, a multicentre comparative study of the upconversion quantum efficiencies of LiYF4 UCNPs is reported. Finally, it describes the formation of water-dispersible UCNPs decorated with the newly-developed ruthenium complexes, as well as their stability in aqueous media and the successful photo-activation of the surface-bound ruthenium complexes using near-infrared light. The work has resulted in new insights into the design principles that are essential for the successful development of photo-activatable ruthenium-decorated upconverting nanoparticles. Show less
Siewert, B.; Langerman, M.; Pannwitz, A.; Bonnet, S.A. 2018
The main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first... Show moreThe main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first investigated whether non-toxic ligands such as L-proline, 2-(methylthio)methylpyridine (mtmp), or 3-(methylthio)propylamine (mtpa), once coordinated to ruthenium(II) complexes, could be photosubstituted upon visible light irradiation. The lipophilicity, and in some cases the strain of the ruthenium(II) complexes, were systematically varied and the effects of such variations on the cytotoxicity of the complexes in the dark and under light irradiation were studied. In the second part, the best ligand candidates (i.e. mtmp and mtpa) were coordinated to cyclometalated ruthenium complexes of the type [Ru(bpy)(phpy)(S,N)]PF6 (bpy = 2,2’-bipyridine and phpy = 2-phenylpyridine), to shift the absorption of the complex to the red region of the spectrum. The photosubstitution properties of these cyclometallated complexes were investigated in detail. The most promising ruthenium complexes were tested in cancer cell monolayers under hypoxic conditions (1% O2) to investigate their mode of action and distinguish between PACT and PDT. Show less
Conventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing... Show moreConventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing a possible solution for this problem. This dissertation describes the synthesis and biological applications of (blue/green/red) light-activated ruthenium polypyridyl drugs as potential prodrugs against cancer. Show less
The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity... Show moreThe field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. In this work we present alternative strategies such as light-activation with different transition-metals such as ruthenium and palladium that have the potential to be more selective than cisplatin type of drugs. Show less
The study of gas-surface interaction dynamics is important both for the fundamental knowledge it provides and also to aid the development of applications involving processes such as sputtering,... Show moreThe study of gas-surface interaction dynamics is important both for the fundamental knowledge it provides and also to aid the development of applications involving processes such as sputtering, plasma etching and heterogeneous catalysis. Elementary steps in the interactions, such as chemical reactions, adsorption and scattering are prototypical of more complex processes and better understanding of them deepens our knowledge of such processes. In addition, experimental measurements of specific interactions can be used to validate advanced computer models. Hence the experiments in this thesis have been carried out under well-defined condition, namely in ultrahigh vacuum and using high-purity single-crystal samples. The thesis is primarily focussed on understanding the interaction of hyperthermal Ar and N (~4-6 eV) with Ru(0001) and Ag(111) via scattering studies. Ar is very inert and its interaction with surfaces is primarily repulsive in nature, while N atoms probe the surface chemisorption well. From the study of Ar scattering dynamics, surface properties have been probed. From N scattering studies, chemisorption dynamics have been investigated. It is found that the electronic state of the incident particle may play an important role in the gas-surface interaction. Separately, the influence of pre-adsorbed CO on Ru(0001) on D2 dissociation have been unravelled. Show less
An industrially applicable process was developed for the synthesis of epoxy resin components. A catalytic reaction was explored towards allyl phenyl ethers that prevents the use of chloride... Show moreAn industrially applicable process was developed for the synthesis of epoxy resin components. A catalytic reaction was explored towards allyl phenyl ethers that prevents the use of chloride-containing starting materials and thus formation of chloride-containing side products. The preferred allylating agent is allyl alcohol or its derivatives since this only produces water as a side product. Ruthenium and palladium complexes were used as catalysts and their structure proved to be of key importance for the outcome of the reaction. By fine-tuning the catalyst structure with phosphine ligands, the reaction could be performed highly selective. Besides the homogeneous catalytic system, also retrieval of the catalyst was studied and the scope of the reaction was explored. Show less
The thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA... Show moreThe thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA-binding properties__. The studies have been carried out using a variety of techniques. Study of the in vitro cytotoxicity against human tumour cell lines along with cellular uptake has been the pivotal point of this research. Synthetic methodologies of the new complexes have been designed to establish structure-activity relation in several series of related complexes. Platinum complexes of derivatized-phenanthroline, pyridine and pyrimidine, have been synthesized and studied in detail for their biological activity. These complexes are different in structure and in overall charges, and were studied to elucidate the effects on the activity profile. A self-activating copper-complex formed from a unique amino-phenol ligand (Hpyramol) inspired the synthesis of platinum and ruthenium analogues. Biological studies including cellular uptake, conformational changes (CD and UV) and DNA cleavage have been performed to interpret the changes in activity profile upon various metal additions. Ruthenium complexes are known as suitable candidates for anticancer (specially as antimetastatic drugs) agents. A group of ruthenium(III) complexes has been studied for their anticancer activity and their DNA-binding properties. The extensive area of homo- or heterometallic dinuclear compounds opens up an interesting challenge towards the synthesis of complexes. The studies of different combinations viz., Ru-Ru, Cu-Cu and Pt-Pt, have been performed to design new series of anticancer complexes. Show less
The design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new... Show moreThe design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new drugs is even higher, considering the high cancer-prevalence rate in our society. The therapeutic application of metal complexes is an under-developed area of research and basic principles in the development of metallopharmaceuticals are lacking, or at least just recently being discovered. Metal-containing agents may offer unique therapeutic opportunities. However, significant obstacles, including potential metal accumulations and toxicities, require further research before a promising metal compound may be introduced in the clinic. In particular several ruthenium and gold coordination compounds have shown promising application as anticancer agents. In these terms, this thesis project, performed in the Coordination and Bioinorganic Chemistry group in the Leiden Institute of Chemistry, comprises the design, synthesis, detailed characterization (i.e. elemental analysis, UV-Vis spectroscopy, IR, far-IR, NMR, mass spectroscopy and X-ray single-crystal structure determination) and also the biological evaluation of novel gold compounds and ruthenium compounds. The promising cytotoxic activity developed for several of these compounds and the findings from this research are providing a better understanding of chemistry of Ru(III) and Ru(II) and Au(III) coordination compounds and their structure-activity relationships and may lead to the development of improved ruthenium and gold-chemotherapeutic drugs. Show less
Cancer is a leading cause of death worldwide. Nowadays, the treatment of cancer by chemotherapy can consist of a combination of antitumor drugs. Nevertheless, chemotherapy is accompanied by serious... Show moreCancer is a leading cause of death worldwide. Nowadays, the treatment of cancer by chemotherapy can consist of a combination of antitumor drugs. Nevertheless, chemotherapy is accompanied by serious side effects and intrinsic and acquired resistance to the drugs. This thesis describes the design and synthesis of novel potential antitumor drugs that combine two different mechanisms of action. One of the two active units is derived from cisplatin, which cured Lance Armstrong?s testicular cancer. This platinum compound is known to induce a distortion of the DNA helix upon binding, resulting in the death of the cancer cells. The second active moiety is based on Cu(3-Clip-Phen), which is a highly active nuclease agent. In other words, the platinum moiety act as an antitumor drug and as an anchor to DNA, while the copper unit cleaves the DNA strand in the close proximity of the platinum-DNA adducts. The two active units have been covalently coupled with a (in)flexible bridge aiming at a synergistic action of the two drugs. The cleaving activity of some of the complexes is higher compared to Cu(3-Clip-Phen). Moreover, three of the new complexes have been found to show equivalent or higher cytotoxicities compared to cisplatin or Cu(3-Clip-Phen). Show less
The perfect anticancer drug would kill cancer cells without causing any harm to the surrounding healthy tissues. That ideal medicine is searched for in this thesis, in the form of a ruthenium... Show moreThe perfect anticancer drug would kill cancer cells without causing any harm to the surrounding healthy tissues. That ideal medicine is searched for in this thesis, in the form of a ruthenium coordination complex.Metal complexes are known to interact with DNA in several different modes, amongst which are coordination, intercalation of the aromatic part of the molecule between the DNA base-pairs and binding of the complex to one of the DNA grooves.Is there a correlation between the ruthenium–DNA interactions and the cytotoxicity of these complexes? Three ruthenium polypyridyl complexes (1a-c) were synthesized and characterized, which can coordinate to guanine. The structure-related 1e and 1f, as well as the dinuclear complex 1g, were also chosen for these studies. The interactions between each ruthenium complex and DNA were studied; the activities of the compounds in different cancer cells were tested.The results of these tests suggest that 1a-c and 1e coordinate to DNA, while 1g probably fits in the DNA groove. These complexes display moderate activity in some cancer cell lines. The inactive complex 1f can coordinate to guanine and bind to DNA via intercalation or groove-binding. 1f is the only one of the studied compounds that lacks an azo group, which suggests that this group is essential for cytotoxicity.The interactions between metal complexes and other biological molecules are also mentioned. Show less
The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents.... Show moreThe research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long and flexible linker. The complexes are characterized and have been studied for anticancer activity. The ruthenium unit of the dinuclear complexes varies in molecular structure, which may result in different interactions with DNA, the target of anticancer platinum and ruthenium antitumor compounds. The monofunctional ruthenium unit coordinates to the DNA-model base 9-ethylguanine. Variable temperature 1H NMR experiments prove that the base is hindered in its free rotation at room temperature. The crystal structure of a dinuclear ruthenium-platinum complex shows that the platinum unit is capable of intercalation and coordination (in)to DNA. Trinuclear and tetranuclear ruthenium and ruthenium-platinum complexes show higher activity than the dinuclear derivatives. A tetranuclear ruthenium complex displays interesting biological features. Human ovarian cisplatin sensitive carcinoma cells adhere together and form clots upon incubation of the complex. The effect possibly indicates antimetastatic activity. Dinuclear and trinuclear ruthenium-platinum complexes of short and semi-rigid linkers do not show significant activity against different cancer cell lines. Show less
