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Alnabulsi S.,University of Manchester | Santina E.,University of Manchester | Russo I.,University of Manchester | Hussein B.,University of Manchester | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2016

NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6 nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies. © 2016 Elsevier Masson SAS.

Jeanmaire D.,University of Manchester | Timco G.A.,University of Manchester | Gennari A.,University of Manchester | Sproules S.,University of Manchester | And 5 more authors.
Chemical Communications | Year: 2015

A new nano contrast agent has been prepared incorporating a molecular magnet in oxidation-responsive nanoparticles; this system has shown a remarkable sensitivity to hydrogen peroxide (detection down to at least 40 μM), which was used as a model reactive oxygen species. Surprisingly, the response had a binary (off/on) character, due to a non-linear cascade relation between extent of oxidation and water permeability in the particles. © The Royal Society of Chemistry 2015.

Gordon G.S.D.,University of Cambridge | Joseph J.,University of Cambridge | Joseph J.,Cancer Imaging Center in Cambridge and Manchester | Bohndiek S.E.,University of Cambridge | And 2 more authors.
Journal of Lightwave Technology | Year: 2015

In this paper, a novel single-pixel method for coherent imaging through an endoscopic fiber bundle is presented. The use of a single-pixel detector allows greater sensitivity over a wider range of wavelengths, which could have significant applications in an endoscopic fluorescence microscopy. First, the principle of lensless focussing at the distal end of a coherent fiber bundle is simulated to examine the impact of pixelation at microscopic scales. Next, an experimental optical correlator system using spatial light modulators is presented. A simple contrast imaging method of characterizing and compensating phase aberrations introduced by fiber bundles is described. Experimental results are then presented showing that our phase compensation method enables characterization of the optical phase profile of individual fiberlets. After applying this correction, early results demonstrating the ability of the system to electronically adjust the focal plane at the distal end of the fiber bundle are presented. The structural similarity index between the simulated image and the experimental focus-adjusted image increases noticeably when the phase correction is applied and the retrieved image is visually recognizable. Strategies to improve image quality are discussed. © 1983-2012 IEEE.

Fleming I.N.,Biomedical Imaging Center | Manavaki R.,University of Cambridge | Blower P.J.,Kings College London | West C.,University of Manchester | And 8 more authors.
British Journal of Cancer | Year: 2015

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers. © 2015 Cancer Research UK. All rights reserved.

Gieling R.G.,University of Manchester | Gieling R.G.,Cancer Imaging Center in Cambridge and Manchester | Fitzmaurice R.J.,Royal Infirmary | Telfer B.A.,University of Manchester | And 3 more authors.
Clinical and Experimental Metastasis | Year: 2015

Complications associated with the development of lung metastases have a detrimental effect on the overall survival rate of many cancer patients. Preclinical models that mimic the clinical aspects of lung metastases are an important tool in developing new therapy options for these patients. The commonly used intravenous models only recapitulate dissemination of cancer cells to the lungs via the haematological route. Here we compared spontaneous and intravenous lung metastases of the highly metastatic KHT mouse fibrosarcoma cells after injecting KHT cells into the subcutaneous layer of the skin or directly into the tail vein. In contrast to the intravenous model, metastases spontaneously arising from the subcutaneous tumours disseminated most consistent with the lymph nodes/lymphatics route and were more hypoxic than the metastases observed following tail-vein administration and haematological spread. To ascertain whether this impacted on drug response, we tested the effectiveness of the hypoxia-sensitive cytotoxin AQ4N (Banoxantrone) in both models. AQ4N was more effective as an anti-metastatic drug in mice with subcutaneous KHT tumours, significantly reducing the metastatic score. Complementing the KHT studies, pathology studies in additional models of spontaneous lung metastases showed haematological (HCT116 intrasplenic implant) or mixed haematological/lymphatic (B16 intradermal implant) spread. These data suggest that preclinical models can demonstrate differing, clinically relevant dissemination patterns, and that careful selection of preclinical models is required when evaluating new strategies for targeting metastatic disease. © 2015, Springer Science+Business Media Dordrecht.

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