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

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

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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Exploring the molecular mechanism of hA1-1 glutathione S-transferase, focusing on the role of the characteristic C-terminal helix.

The molecular mechanism of hAl-1 glutathione S-transferase (GST) has been probed using fluorescence and NMR spectroscopy, kinetic analysis and X-ray crystallography. The results show that the mechanism of hAl-1 GST involves hydrophobic substrate activation, and the efficiency of this process is a crucial factor in hydrophobic substrate specificity. Hydrophobic substrate activation can only occur when the glutathione peptidyl moiety has bound, inducing a conformational change in the protein. The main region of the protein that is involved in this conformational change is the characteristic C-terminal helix of hAl-1 GST and the integrity of this region has been shown to be essential for hydrophobic substrate activation. It is thought that the C-terminal helix correctly orientates the hydrophobic substrate in the active site allowing activation to occur. The deletion of the C-terminal helix alters the substrate specificity of the enzyme, with the truncated enzyme having a high activity towards ethacrynic acid, normally a pi-class GST substrate. Thus the characteristic C-terminal helix of alpha class GSTs is a major determinant in substrate specificity, in particular determining the characteristic substrate specificity of hAl-1 GST

Vector Control in Developing Countries: Challenges and Solutions

Undoubtedly, reducing vector populations or their interactions with hosts below a critical level is a practical and proven method of disease control. Introduction of insecticide-treated bed nets has significantly reduced malaria in some parts of the world. However, for many reasons, implementation of such strategies is challenging and the protection offered by particular products limited: bed nets are only effective during sleep. Other methods have been launched, but low customer appeal, high cost, low specificity, and lack of sustainability and effectiveness are often reasons for failure. The proposed solution to these problems should also consider safety and environmental impact and be forward-thinking for continued functioning in a rapidly changing local environment. To this end, a chemical system has been identified that could be used to make an autonomous trap with chemo-attractant system

CCDC 161466: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

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

The hydrolysis of [Ru(η6-p-cymene)Cl2(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(η6-p-cymene)Cl(H2O)(PTA)]+ was the most abundant hydrolysis product, although the dihydrolyzed species [Ru(η6-p-cymene)(OH)(H2O)(PTA)]+ and the dichloro compd. are present. Rate consts. for the different aquation and anation steps and the equil. consts. were detd. Hydrolysis is suppressed at high chloride concns. These results have important implications on the mode of action of the RAPTA drug candidates