Claire S. Allardyce

Synthesis and characterisation of some water soluble ruthenium(II)-arene complexes and an investigation of their antibiotic and antiviral properties

The water soluble ruthenium-p-cymene complexes [Ru(eta(6)-p-cymene)X-2](2) (X = Cl, Br, I or NCS), [Ru(eta(6)-p-cymene)X-2(pta)] (X=Cl, Br, I, or NCS; pta=1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) and the tetraruthenium cluster [H4Ru4(eta(6)-p-benzene)(4)](2+) have been prepared and their antimicrobial properties evaluated. They have been screened for antibacterial activity against Eschericia coli, Bascillus subtilis, Pseudomonas aeruginos, for antifungal activity against Candida albicans, Cladosporium resinae and Trichrophyton mentagrophytes and for antiviral activity against Herpes simplex and Polio viruses. The antimicrobial activity of these compounds does not appear to be correlated to DNA binding, but it could be due to specific interactions with proteins. The solid-state structure of the dimer complex [Ru(eta(6)-p-cymene)Cl-2](2), an important precursor complex in organometallic chemistry, is also reported

Hydrolysis study of the bifunctional antitumour compound RAPTA-C, [Ru(η6-p-cymene)Cl2(pta)]

The hydrolysis of [Ru(eta(6)-p-cymene)Cl(2)(PTA)] (PTA=1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decanephosphine; RAPTA-C) was studied using UV-visible (UV-vis) spectrophotometry and NMR spectroscopy. In analogy to in silico studies, [Ru(eta(6)-p-cymene)Cl(H(2)O)(PTA)](+) was found to be the most abundant hydrolysis product, although the dihydrolysed species [Ru(eta(6)-p-cymene)(OH)(H(2)O)(PTA)](+) and the dichloro compound are present. Rate constants for the different aquation and anation steps and the equilibrium constants were determined. Hydrolysis is suppressed at high chloride concentrations. These results have important implications on the mode of action of the RAPTA drug candidates.

Metal-based drugs that break the rules

Cisplatin and other platinum compounds have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The success of these compounds has biased the approaches used to discover new metal-based anticancer drugs. In this perspective we highlight compounds that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compound design and the approaches used to validate their utility. Possible design approaches for the future are also suggested.

A mass spectrometric and molecular modelling study of cisplatin binding to transferrin

A combination of mass spectrometry, UV/Vis spectroscopy and molecular modelling techniques have been used to characterise the interaction of cisplatin with human serum transferrin (Tf). Mass spectrometry indicates that cisplatin binds to the hydroxy functional group of threonine 457, which is located in the iron(III)‐binding site on the C‐terminal lobe of the protein. UV/Vis spectroscopy confirms the stoichiometry of binding and shows that cisplatin and iron(III) binding are competitive. The binding of cisplatin has been modelled by using molecular dynamic simulations and the results suggest that cisplatin can occupy part of both the iron(III)‐ and carbonate‐binding sites in the C‐terminal lobe of the protein. Combined, the studies suggest that cisplatin binding sterically restricts iron(III) binding to the C‐terminal lobe binding site, whereas the N‐terminal lobe binding site appears to be unaffected by the cisplatin interaction, possibly allowing the iron(III)‐induced conformational change necessary for binding to a Tf receptor.

Expression proteomics study to determine metallodrug targets and optimal drug combinations

The emerging technique termed functional identification of target by expression proteomics (FITExP) has been shown to identify the key protein targets of anti-cancer drugs. Here, we use this approach to elucidate the proteins involved in the mechanism of action of two ruthenium(II)-based anti-cancer compounds, RAPTA-T and RAPTA-EA in breast cancer cells, revealing significant differences in the proteins upregulated. RAPTA-T causes upregulation of multiple proteins suggesting a broad mechanism of action involving suppression of both metastasis and tumorigenicity. RAPTA-EA bearing a GST inhibiting ethacrynic acid moiety, causes upregulation of mainly oxidative stress related proteins. The approach used in this work could be applied to the prediction of effective drug combinations to test in cancer chemotherapy clinical trials.

Light in Medicine: The Interplay of Chemistry and Light.

Photodynamic therapy (PDT) has had mixed reception in the clinic, with most success stories being based on the ablative capacity of PDT. In these applications, maximal combinations of light and an exogenous photosensitiser are used to generate high levels of reactive oxygen species (ROS) that induce cell death either directly via necrosis or indirectly via vascular damage. However, recent advances in understanding the complex role of ROS in cell signalling have revealed potential new applications for PDT. For example, the proliferative effects of low level ROS could be applied to wound healing or immunomodulation. These effects should also be considered in the ablative applications. With the decades of chemical advances for ablative PDT at hand - including targeting mechanisms to diseased cells and subcellular locations, optimisation of light absorption, and carrier mechanisms that modulate the therapeutic response - the application of PDT to other types of treatment could be relatively rapid. This review serves to summarise some of these developments and suggest future directions.Photodynamic therapy (PDT) has had mixed reception in the clinic, with most success stories being based on the ablative capacity of PDT. In these applications, maximal combinations of light and an exogenous photosensitiser are used to generate high levels of reactive oxygen species (ROS) that induce cell death either directly via necrosis or indirectly via vascular damage. However, recent advances in understanding the complex role of ROS in cell signalling have revealed potential new applications for PDT. For example, the proliferative effects of low level ROS could be applied to wound healing or immunomodulation. These effects should also be considered in the ablative applications. With the decades of chemical advances for ablative PDT at hand - including targeting mechanisms to diseased cells and subcellular locations, optimisation of light absorption, and carrier mechanisms that modulate the therapeutic response - the application of PDT to other types of treatment could be relatively rapid. This review serves to summarise some of these developments and suggest future directions.