• An alternative synthesis of Vandetanib (CaprelsaTM) via a microwave accelerated Dimroth rearrangement

      Brocklesby, K.L.; Waby, Jennifer S.; Cawthorne, C.; Smith, G. (2017-04-12)
      Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
    • Apolipoprotein E ε4 allele modulates the immediate impact of acute exercise on prefrontal function

      De Marco, M.; Clough, P.J.; Dyer, C.E.; Vince, R.V.; Waby, Jennifer S.; Midgley, A.W.; Venneri, A. (2015-01)
      The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity.
    • A practical microwave method for the synthesis of fluoromethy 4-methylbenzenesulfonate in tert-amyl alcohol

      Brocklesby, K.L.; Waby, Jennifer S.; Cawthorne, C.; Smith, G. (2018-04-25)
      Fluorine substitution is an established tool in medicinal chemistry to favourably alter the molecular properties of a lead compound of interest. However, gaps still exist in the library of synthetic methods for accessing certain fluorine-substituted motifs. One such area is the fluoromethyl group, particularly when required in a fluoroalkylating capacity. The cold fluorination of methylene ditosylate is under evaluated in the literature, often proceeding with low yields or harsh conditions. This report describes a novel microwave method for the rapid nucleophilic fluorination of methylene ditosylate using inexpensive reagents in good isolated yield (65%).
    • Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection

      Evans, C.A.; Rosser, R.; Waby, Jennifer S.; Noirel, J.; Lai, D.; Wright, P.C.; Williams, E.A.; Riley, S.A.; Bury, J.P.; Corfe, B.M. (2015-12-31)
      Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues. A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention. Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level. Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention.
    • Structurally optimised BODIPY derivatives for imaging of mitochondrial dysfunction in cancer and heart cells

      Nigam, S.; Burke, B.P.; Davies, L.H.; Domarkas, J.; Wallis, J.F.; Waddell, P.G.; Waby, Jennifer S.; Benoit, D.M.; Seymour, A.-M.; Cawthorne, C.; et al. (2016-05)
      The structural features required for mitochondrial uptake of BODIPY-based optical imaging agents have been explored. The first derivatives of this class of dyes shown to have mitochondrial membrane potential-dependent uptake in both cancer and heart cells have been developed.