Biomolecular interactions and cellular effects of steroidal and metallosupramolecular metallodrugs

The work described herein concerns the effect on the anticancer activity and the ability to reach their possible intracellular targets of certain steroidal metallodrugs and metallosupramolecular cylinders. Chapter 1 surveys the background to the project, surveying different DNA-binding modes, explaining their importance in the anticancer properties of metallodrugs and showing an overview of the different strategies used for enhanced delivery of these metallodrugs. In Chapter 2 the synthesis of new steroidal DNA covalent-binding platinum(II) complexes together with techniques to purify previously synthesised steroidal complexes are presented. Their cytotoxicity, cellular uptake and biomolecular interaction are investigated, showing that the coupling of the steroid confers activity to otherwise inactive complexes, modifying their DNA binding mode and cellular uptake and distribution. Chapter 3 explores the coupling of similar steroidal delivery vectors to non-covalent metallodrugs, presenting simple synthetic pathways to create such complexes in a single step. Their anticancer activity and DNA-binding affinity are investigated: surprisingly showing that this coupling has negative effects. In Chapter 4 the cytoxicity and cellular behaviour of metallosupramolecular cylinders are studied. It is shown that these complexes can cross the cellular membrane, concentrating in the nuclei where they can interact with cellular DNA

Glutathione activation of an organometallic half-sandwich anticancer drug candidate by ligand attack

Density functional theory calculations and X-ray absorption spectroscopic data suggest an unusual activation mechanism for this potent Os anticancer complex: catalytic attack by intracellular thiol glutathione on the azo bond of the chelated ligand

Easy to synthesize, robust organo-osmium asymmetric transfer hydrogenation catalysts

Asymmetric transfer hydrogenation (ATH) is an important process in organic synthesis for which the Noyori-type RuII catalysts [(arene)Ru(Tsdiamine)] are now well established and widely used. We now demonstrate for the first time the catalytic activity of the osmium analogues. X-ray crystal structures of the 16-electron OsII catalysts are almost identical to those of RuII. Intriguingly the precursor complex was isolated as a dichlorido complex with a monodentate amine ligand. The OsII catalysts are readily synthesised (within 1 h) and exhibit excellent enantioselectivity in ATH reactions of ketones

Well-defined hyperstar copolymers based on a thiol–yne hyperbranched core and a poly(2-oxazoline) shell for biomedical applications

Well defined ‘hyperstar’ copolymers were synthesized by combining hyperbranched polymers produced by thiol–yne chemistry with poly(oxazoline)s. The hyperbranched core was prepared using an AB2 monomer and a trifunctional alkene, applying a monomer feeding approach. The degree of branching was high (0.9) while maintaining low dispersities (1.3). Poly(2-ethyl-2-oxazoline) (PEtOx) functionalized with a thiol end group was coupled to the surface of the hyperbranched structure accessing terminal alkyne units. PEtOx-SH was produced by the termination of the living polymerization with ethyl xanthate and subsequent conversion to thiol under alkaline conditions. The degree of polymerization was varied producing PEtOx with 23 or 42 repeating units, respectively with a dispersity of around 1.1. After conjugation of the polymer arms, hyperstar copolymers were characterized by SEC, NMR spectroscopy, light scattering, and AFM. The polymers were able to encapsulate the hydrophobic dye Nile red within the core of the structure with loading efficiencies between 0.3 and 0.9 wt%. Cytotoxicity of the hyperstars was assessed using A2780 human ovarian carcinoma cells resulting in IC50 values of around 0.7 mg ml−1. Successful internalization and colocalization with lysosomal compartments was observed by confocal microscopy studies

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

Catalytic anticancer metallodrugs active at low doses could minimise side-effects, introduce novel mechanisms of action which combat resistance, and widen the spectrum of anticancer drug activity. We have used new highly-stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] to achieve highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways, both in aqueous model systems and in human cancer cells, using non-toxic concentrations of sodium formate as a hydride source. Importantly the catalytic mechanism generates selectivity towards ovarian cancer cells versus non-cancerous fibroblasts (both ovarian and lung), which are commonly used as models of healthy proliferating cells. The formate precursor N-formylmethionine was explored as an alternative to formate in PC3 prostate cancer cells, which are known to over-express a deformylase enzyme. Transfer hydrogenation catalysts generating reductive stress in cancer cells offer a ground-breaking new approach to cancer therapy

Flood Resilience Assessment In Urban Drainage Systems Through Multi-Objective Optimisation

In future years, economic development, urbanisation and heavy rainfall events are expected to increase in urban areas, in particular in developing countries. It is well known that urban development has a strong impact on the water cycle such as increase of flood peaks and volume, decrease of base flow, hydraulic stress and water pollution. Resilience measures are still needed to improve urban flood risk, the possibilities to provide indicators that could be used to characterize urban resilience related to flooding is outmost importance. The work described here presents an optimisation framework for urban drainage rehabilitation that incorporates in the decision space the concept of resilience in order to find an optimal rehabilitation strategy. The approach has been tested in the City of Dhaka, Bangladesh by coupling 1D/2D model of the drainage system and linked within the optimisation algorithm. The preliminary results obtained suggest that the proposed approach could be effective in order to reach acceptable level of flood resilience of urban drainage systems, balancing investment and risk within the systems. Further work is recommended to expand and generalize the methodology

Der „neue“ Münzfundkatalog Mittelalter/Neuzeit der Numismatischen Kommission der Länder in der Bundesrepublik Deutschland (Ein Zwischenbericht)

Im Jahre 1941 erschien in den Blättern für deutsche Landesgeschichte ein programmatischer Aufsatz über „Die deutschen Münzfunde“. Autor war der Braunschweiger Museumsdirektor Prof. Dr. Wilhelm Jesse (1887–1972). Er gehörte zu den ersten Mitgliedern der 1943 gegründeten Braunschweigischen Wissenschaftlichen Gesellschaft. Seine Ideen zur Fundnumismatik inspirierten bald Walter Hävernick (1905–1983) zu seiner Konzeption einer flächendeckenden Funddokumentation für Thüringen (1943/1955) und Deutschland (1950). Aus dem maschinenschriftlichen Fundkatalog Mittelalter/Neuzeit "seiner" Numismatischen Kommission der Länder in der Bundesrepublik Deutschland ist ein halbes Jahrhundert später der EDV-Münzfundkatalog hervorgegangen