• Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2

      Hamdy, Rania; Elseginy, Samia; Ziedan, Noha; El-Sadek, Mohamed; Lashin, El-Said; Jones, Arwyn T; Westwell, Andrew D; University of Chester; Cardiff University; Zagazig University; Bristol University; University of Sharjah
      A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent.
    • Fibre laser treatment of beta TNZT titanium alloys for load-bearing implant applications: Effects of surface physical and chemical features on mesenchymal stem cell response and Staphylococcus aureus bacterial attachment

      Donaghy, Clare L.; McFadden, Ryan; Smith, Graham C.; Kelaini, Sophia; Carson, Louise; Malinov, Savko; Margariti, Andriana; Chan, Chi-Wai; Queens University Belfast; University of Chester (MDPI, 2019-03-12)
      A mismatch in bone and implant elastic modulus can lead to aseptic loosening and ultimately implant failure. Selective elemental composition of titanium (Ti) alloys coupled with surface treatment can be used to improve osseointegration and reduce bacterial adhesion. The biocompatibility and antibacterial properties of Ti-35Nb-7Zr-6Ta (TNZT) using fibre laser surface treatment were assessed in this work, due to its excellent material properties (low Young’s modulus and non-toxicity) and the promising attributes of fibre laser treatment (very fast, non-contact, clean and only causes changes in surface without altering the bulk composition/microstructure). The TNZT surfaces in this study were treated in a high speed regime, specifically 100 and 200 mm/s, (or 6 and 12 m/min). Surface roughness and topography (WLI and SEM), chemical composition (SEM-EDX), microstructure (XRD) and chemistry (XPS) were investigated. The biocompatibility of the laser treated surfaces was evaluated using mesenchymal stem cells (MSCs) cultured in vitro at various time points to assess cell attachment (6, 24 and 48 h), proliferation (3, 7 and 14 days) and differentiation (7, 14 and 21 days). Antibacterial performance was also evaluated using Staphylococcus aureus (S. aureus) and Live/Dead staining. Sample groups included untreated base metal (BM), laser treated at 100 mm/s (LT100) and 200 mm/s (LT200). The results demonstrated that laser surface treatment creates a rougher (Ra value of BM is 199 nm, LT100 is 256 nm and LT200 is 232 nm), spiky surface (Rsk > 0 and Rku > 3) with homogenous elemental distribution and decreasing peak-to-peak distance between ripples (0.63 to 0.315 m) as the scanning speed increases (p < 0.05), generating a surface with distinct micron and nano scale features. The improvement in cell spreading, formation of bone-like nodules (only seen on the laser treated samples) and subsequent four-fold reduction in bacterial attachment (p < 0.001) can be attributed to the features created through fibre laser treatment, making it an excellent choice for load bearing implant applications. Last but not least, the presence of TiN in the outermost surface oxide might also account for the improved biocompatibility and antibacterial performances of TNZT.
    • Graphene Oxide Bulk Modified Screen-Printed Electrodes Provide Beneficial Electroanalytical Sensing Capabilities

      Rowley-Neale, Samuel; Brownson, Dale; Smith, Graham; Banks, Craig; Manchester Metropolitan University; University of Chester (MDPI, 2020-03-19)
      We demonstrate a facile methodology for the mass production of graphene oxide (GO) bulk modified screen-printed electrodes (GO-SPEs) that are economical, highly reproducible and provide analytically useful outputs. Through fabricating GO-SPEs with varying percentage mass incorporations (2.5, 5, 7.5 and 10%) of GO, an electrocatalytic effect towards the chosen electroanalytical probes is observed, that increases with greater GO incorporated compared to bare/ graphite SPEs. The optimum mass ratio of 10% GO to 90% carbon ink displays an electroanalytical signal towards dopamine (DA) and uric acid (UA), which is ca. ×10 greater in magnitude than that achievable at a bare/unmodified graphite SPE. Furthermore, 10% GO-SPEs exhibit a competitively low limit of detection (3σ) towards DA at ca. 81 nM, which is superior to that of a bare/unmodified graphite SPE at ca. 780 nM. The improved analytical response is attributed to the large number of oxygenated species inhabiting the edge and defect sites of the GO nanosheets, which are available to exhibit electrocatalytic responses towards inner-sphere electrochemical analytes. Our reported methodology is simple, scalable, and cost effective for the fabrication of GO-SPEs, that display highly competitive LODs, and is of significant interest for use in commercial and medicinal applications
    • New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2

      Hamdy, Rania; Elseginy, Samia A.; Ziedan, Noha I.; Jones, Arwyn T.; Westwell, Andrew D. (MDPI, 2019-04-02)
      The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-N-arylhydrazine-1-carbothioamide (5a⁻b) intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound 6i) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC50 activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of 6i was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.
    • Pencil It In: Exploring the Feasibility of Hand-drawn Pencil Electrochemical Sensors and their Direct Comparison to Screen-printed Electrodes

      Bernalte, Elena; Foster, Christopher W.; Brownson, Dale A. C.; Mosna, Morgane; Smith, Graham C.; Banks, Craig E.; Manchester Metropolitain University (Foster, Brownson, Mosna, Banks), Universidad de Extremadura, Badajoz (Bernalte), University of Chester (Smith) (MDPI, 2016-08-29)
      We explore the fabrication, physicochemical characterisation (SEM, Raman, EDX and XPS) and electrochemical application of hand-drawn pencil electrodes (PDEs) upon an ultra-flexible polyester substrate; investigating the number of draws (used for their fabrication), the pencil grade utilised (HB to 9B) and the electrochemical properties of an array of batches (i.e, pencil boxes). Electrochemical characterisation of the PDEs, using different batches of HB grade pencils, is undertaken using several inner- and outer-sphere redox probes and is critically compared to screen-printed electrodes (SPEs). Proof-of-concept is demonstrated for the electrochemical sensing of dopamine and acetaminophen using PDEs, which are found to exhibit competitive limits of detection (3 ) upon comparison to SPEs. Nonetheless, it is important to note that a clear lack of reproducibility was demonstrated when utilising these PDEs fabricated using the HB pencils from different batches. We also explore the suitability and feasibility of a pencil-drawn reference electrode compared to screen-printed alternatives, to see if one can draw the entire sensing platform. This article reports a critical assessment of these PDEs against that of its screen-printed competitors, questioning the overall feasibility of PDEs’ implementation as a sensing platform.
    • A preliminary study to enhance the tribological performance of CoCrMo alloy by laser remelting for articular joint implant applications

      Chan, Chi-Wai; Smith, Graham C.; Lee, Seunghwan; Queens University Belfast; University of Chester; Technical University Denmark (MDPI, 2018-03-02)
      CoCrMo alloy has long been used as a pairing femoral head material for articular joint implant applications because of its biocompatibility and reliable tribological performance. However, friction and wear issues are still present for CoCrMo (metal)/CoCrMo (metal) or CoCrMo (metal)/ultrahigh molecular weight polyethylene (UHMWPE) (plastic) pairs in clinical observations. The particulate wear debris generated from the worn surfaces of CoCrMo or UHMWPE can pose a severe threat to human tissues, eventually resulting in the failure of implants and the need for revision surgeries. As a result, a further improvement in tribological properties of this alloy is still needed, and it is of great interest to both the implant manufacturers and clinical surgeons. In this study, the surface of CoCrMo alloy was laser-treated by a fibre laser system in an open-air condition (i.e., no gas chamber required). The CoCrMo surfaces before and after laser remelting were analysed and characterised by a range of mechanical tests (i.e., surface roughness measurement and Vickers micro-hardness test) and microstructural analysis (i.e., XRD phase detection). The tribological properties were assessed by pin-on-disk tribometry and dynamic light scattering (DLS). Our results indicate that the laser-treated surfaces demonstrated a friction-reducing effect for all the tribopairs (i.e., CoCrMo against CoCrMo and CoCrMo against UHHMWPE) and enhanced wear resistance for the CoCrMo/CoCrMo pair. Such beneficial effects are chiefly attributable to the presence of the laser-formed hard coating on the surface. Laser remelting possesses several competitive advantages of being a clean, non-contact, fast, highly accurate and automated process compared to other surface coating methods. The promising results of this study point to the possibility that laser remelting can be a practical and effective surface modification technique to further improve the tribological performance of CoCr-based orthopaedic implants.