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  • Journal article
    Boltersdorf T, Gavins FNE, Long NJ, 2021,

    Long-lived lanthanide emission via a pH-sensitive and switchable LRET complex

    , CHEMICAL SCIENCE, ISSN: 2041-6520
  • Journal article
    Walter E, Ge Y, Mason J, Boyle J, Long Net al., 2021,

    A coumarin-porphyrin FRET break-apart probe for heme oxygenase-1

    , Journal of the American Chemical Society, Vol: 143, Pages: 6460-6469, ISSN: 0002-7863

    Heme oxygenase-1 (HO-1) is a vital enzyme in humans that primarily regulates free heme concentrations. The overexpression of HO-1 is commonly associated with cardiovascular and neurodegenerative diseases including atherosclerosis and ischemic stroke. Currently, there are no known chemical probes to detect HO-1 activity, limiting its potential as an early diagnostic/prognostic marker in these serious diseases. Reported here are the design, synthesis, and photophysical and biological characterization of a coumarin–porphyrin FRET break-apart probe to detect HO-1 activity, Fe–L1. We designed Fe–L1 to “break-apart” upon HO-1-catalyzed porphyrin degradation, perturbing the efficient FRET mechanism from a coumarin donor to a porphyrin acceptor fluorophore. Analysis of HO-1 activity using Escherichia coli lysates overexpressing hHO-1 found that a 6-fold increase in emission intensity at 383 nm was observed following incubation with NADPH. The identities of the degradation products following catabolism were confirmed by MALDI-MS and LC–MS, showing that porphyrin catabolism was regioselective at the α-position. Finally, through the analysis of Fe–L2, we have shown that close structural analogues of heme are required to maintain HO-1 activity. It is anticipated that this work will act as a foundation to design and develop new probes for HO-1 activity in the future, moving toward applications of live fluorescent imaging.

  • Journal article
    Bennett TLR, Wilkinson L, Lok JMA, O'Toole R, Long Net al., 2021,

    Synthesis, electrochemistry and optical properties of highly conjugated alkynyl-ferrocenes and -biferrocenes

    , Organometallics, Vol: 40, Pages: 1156-1162, ISSN: 0276-7333

    Sonogashira reactions are utilized herein to react iodo-ferrocenes and -biferrocenes with terminal alkyne ligands, functionalized with both pyridine and thioanisole groups. High-yielding reactions generate both monoalkynyl and dialkynyl derivatives, the ratio of which can be altered through changes in the reaction stoichiometry. This methodology allowed us to synthesize a large family of derivatives, comprising four symmetrical derivatives (3xx, where x represents a phenyl-substituted terminal alkyne) and six less-studied asymmetrical derivatives (3xy, where x and y represent two different phenyl-substituted terminal alkynes), as well as a number of their biferrocenyl analogues (6x, 7xx, and 7xy), including the first known examples of asymmetrically disubstituted biferrocenes. We examined the electrochemical behavior of all the systems in solution through the use of cyclic voltammetry and demonstrate that these highly conjugated alkynyl ligands exert delicate redox control over the central ferrocene motif. We also note that these substituents display some control over the mixed-valence character present in biferrocene monocations, with thioanisole substituents imparting almost an order of magnitude higher Kc than their pyridyl analogues, and asymmetric systems displaying rare characteristic properties of mixed-valence isomers. The electronic structure of these systems was further elucidated through a combination of UV/vis spectroscopy and density functional theory calculations. Our methodology provides a facile and adaptable route toward the isolation of a number of novel ferrocene and biferrocene derivatives. From our perspective, the asymmetric nature of these systems, along with the delicate and predictable redox control that these ligands exert on the central ferrocene unit(s), could lead to applications in molecular electronics, where these properties have previously shown promise in the fabrication of diodes and rectifiers, as well as in the synthesis of donor

  • Journal article
    Wang X, Ismael A, Almutlg A, Alshammari M, Al-Jobory A, Alshehab A, Bennett TLR, Wilkinson LA, Cohen LF, Long NJ, Robinson BJ, Lambert Cet al., 2021,

    Optimised power harvesting by controlling the pressure applied to molecular junctions

    , Chemical Science, Vol: 12, Pages: 5230-5235, ISSN: 2041-6520

    A major potential advantage of creating thermoelectric devices using self-assembled molecular layers is their mechanical flexibility. Previous reports have discussed the advantage of this flexibility from the perspective of facile skin attachment and the ability to avoid mechanical deformation. In this work, we demonstrate that the thermoelectric properties of such molecular devices can be controlled by taking advantage of their mechanical flexibility. The thermoelectric properties of self-assembled monolayers (SAMs) fabricated from thiol terminated molecules were measured with a modified AFM system, and the conformation of the SAMs was controlled by regulating the loading force between the organic thin film and the probe, which changes the tilt angle at the metal-molecule interface. We tracked the thermopower shift vs. the tilt angle of the SAM and showed that changes in both the electrical conductivity and Seebeck coefficient combine to optimize the power factor at a specific angle. This optimization of thermoelectric performance via applied pressure is confirmed through the use of theoretical calculations and is expected to be a general method for optimising the power factor of SAMs.

  • Journal article
    Farleigh M, Pham TT, Yu Z, Kim J, Sunassee K, Firth G, Forte N, Chudasama V, Baker JR, Long NJ, Rivas C, Ma MTet al., 2021,

    New Bifunctional Chelators Incorporating Dibromomaleimide Groups for Radiolabeling of Antibodies with Positron Emission Tomography Imaging Radioisotopes.

    , Bioconjug Chem

    Positron Emission Tomography (PET) imaging with antibody-based contrast agents frequently uses the radioisotopes [64Cu]Cu2+ and [89Zr]Zr4+. The macrobicyclic chelator commonly known as sarcophagine (sar) is ideal for labeling receptor-targeted biomolecules with [64Cu]Cu2+. The siderophore chelator, desferrioxamine-B (dfo), has been widely used to incorporate [89Zr]Zr4+ into antibodies. Here, we describe new bifunctional chelators of sar and dfo: these chelators have been functionalized with dibromomaleimides (dbm), that enable site-specific and highly stable attachment of molecular cargoes to reduced, solvent-accessible, interstrand native disulfide groups. The new sar-dbm and dfo-dbm derivatives can be easily conjugated with the IgG antibody trastuzumab via reaction with reduced interstrand disulfide groups to give site-specifically modified dithiomaleamic acid (dtm) conjugates, sar-dtm-trastuzumab and dfo-dtm-trastuzumab, in which interstrand disulfides are rebridged covalently with a small molecule linker. Both sar- and dfo-dtm-trastuzumab conjugates have been radiolabeled with [64Cu]Cu2+ and [89Zr]Zr4+, respectively, in near quantitative radiochemical yield (>99%). Serum stability studies, in vivo PET imaging, and biodistribution analyses using these radiolabeled immunoconjugates demonstrate that both [64Cu]Cu-sar-dtm-trastuzumab and [89Zr]Zr-dfo-dtm-trastuzumab possess high stability in biological milieu. Dibromomaleimide technology can be easily applied to enable stable, site-specific attachment of radiolabeled chelators, such as sar and dfo, to native interstrand disulfide regions of antibodies, enabling tracking of antibodies with PET imaging.

  • Journal article
    Omoruyi U, Page SJ, Apps S, White AJP, Long NJ, Miller PWet al., 2021,

    Synthesis and characterisation of a range of Fe, Co, Ru and Rh triphos complexes and investigations into the catalytic hydrogenation of levulinic acid

    , Journal of Organometallic Chemistry, Vol: 935, Pages: 1-12, ISSN: 0022-328X

    The coordination chemistry of the N-triphos ligand (NP3Ph, 1b) has been investigated with range of Fe, Co and Rh precursors and found to form either tridentate or bidentate complexes. Reaction of NP3Ph with [Rh(COD)(CH3CN)2]BF4 resulted in the formation of the tridentate complex [Rh(COD)(κ3 NP3Ph)]BF4 (3) in the solid state, however, in solution a bidentate complex predominates in more polar solvents. Reaction of NP3Ph with Fe carbonyl precursors revealed the formation of the bidentate complexes [Fe(CO)3(κ2-NP3Ph)Fe(CO)4] (4) and [Fe(CO)3(κ2-NP3Ph)] (5), while reaction with FeBr2 resulted in the paramagnetic bidentate complex [Fe(Br)2(κ2-NP3Ph)] (6). Reaction of NP3Ph with CoCl2 gave a dimeric Co species [(κ2-NP3Ph)CoCl(κ1,κ2-NP3Ph)CoCl3] (7), while Zn powder reduction of NP3Ph Co halides resulted in the formation of the tridentate complexes of the type: [Co(X)(k3-NP3Ph)]. The related triphos Ru complex, [Ru(CO3)(CO)(κ3-CP3Ph)] (2), has also been isolated and characterised. Preliminary catalytic hydrogenation of levulinic acid (LA) was conducted with 2 and 3. The Ru complex was found to be catalytically active, giving high conversions of LA to form gamma valerolactone (GVL) and 1,4-pentandiol (1,4-PDO), while 3 was found to be catalytically inactive. In situ catalytic testing with 1b and Fe(BF4)2.6H2O resulted in low conversions of LA while a combination of 1b and Co(BF4)2.6H2O gave higher conversions 75% yields of GVL.

  • Journal article
    Wang C, Sun W, Zhang J, Zhang J, Guo Q, Zhou X, Fan D, Liu H, Qi M, Gao X, Xu H, Gao Z, Tian M, Zhang H, Wang J, Wei Z, Long NJ, Mao Y, Li Cet al., 2021,

    An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy

    , NATURE BIOMEDICAL ENGINEERING, Vol: 5, Pages: 278-289, ISSN: 2157-846X
  • Journal article
    Ismael A, Al-Jobory A, Wang X, Alshehab A, Almutlg A, Alshammari M, Grace I, Bennett TLR, Wilkinson LA, Robinson BJ, Long NJ, Lambert Cet al., 2021,

    Molecular-scale thermoelectricity: as simple as 'ABC' (vol 2, pg 5329, 2020)

    , NANOSCALE ADVANCES, Vol: 3, Pages: 619-619, ISSN: 2516-0230
  • Patent
    Boyle J, Long NJ, Walter ERH, Ge Y, Mason JCet al., 2020,

    COMPOUNDS FOR THE DETECTION OF HEME OXYGENASE 1 (HO-1), AND METHODS AND USES INVOLVING THE SAME

    , 2017871.1

    The present invention relates to compounds for the detection of heme oxygenase 1 (HO-1), in particular porphyrin, chlorin, bacteriochlorin or isobacteriochlorin compounds having a tetrapyrrole or reduced tetrapyrrole backbone and a fluorophore. Such compounds can be used in the detection of HO-1 in vivo, ex vivo and in vitro, and can also be used in methods of diagnosis and as research reagents.

  • Journal article
    Ismael A, Al-Jobory A, Wang X, Alshehab A, Almutlg A, Alshammari M, Grace I, Benett TLR, Wilkinson LA, Robinson BJ, Long NJ, Lambert Cet al., 2020,

    Molecular-scale thermoelectricity: as simple as 'ABC'

    , NANOSCALE ADVANCES, Vol: 2, Pages: 5329-5334, ISSN: 2516-0230
  • Journal article
    Morse SV, Boltersdorf T, Chan TG, Gavins FNE, Choi JJ, Long NJet al., 2020,

    In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia

    , RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679

    To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.

  • Journal article
    Seneviratne A, Han Y, Wong E, Walter E, Jiang L, Cave L, Long NJ, Carling D, Mason JC, Haskard DO, Boyle Jet al., 2020,

    Hematoma resolution in vivo is directed by Activating Transcription Factor 1

    , Circulation Research, Vol: 127, Pages: 928-944, ISSN: 0009-7330

    Rationale: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an adenosine monophosphate activated protein kinase / activating transcription factor 1 (AMPK/ATF1) pathway that directs Mhem macrophages through coregulation of heme oxygenase 1 (HMOX1, HO-1) and lipid homeostasis genes.Objective: We asked whether this pathway had an in vivo role in mice.Methods and Results: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow derived macrophages (mBMM), heme induced HO-1, lipid regulatory genes including LXR, the growth factor IGF1, and the splenic red pulp macrophage gene Spic. This response was lost in mBMM from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between day 8 and day 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-) (n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent.Conclusions: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution.

  • Journal article
    Evans RJ, Lavin B, Phinikaridou A, Chooi KY, Mohri Z, Wong E, Boyle JJ, Krams R, Botnar R, Long NJet al., 2020,

    Targeted molecular iron oxide contrast agents for imaging atherosclerotic plaque

    , Nanotheranostics, Vol: 4, Pages: 184-194, ISSN: 2206-7418

    Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits1. To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo.Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis.Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE-/- mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE-/- mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histo

  • Journal article
    Cohen L, 2020,

    Tuning the thermoelectrical properties of anthracene-based self-assembled monolayers

    , Chemical Science, Vol: 11, Pages: 6836-6841, ISSN: 2041-6520

    It is known that the electrical conductance of single molecules can be controlled in a deterministic manner by chemically varying their anchor groups to external electrodes. Here, by employing synthetic methodologies to vary the terminal anchor groups around aromatic anthracene cores, and by forming self-assembled monolayers (SAMs) of the resulting molecules, we demonstrate that this method of control can be translated into cross-plane SAM-on-gold molecular films. The cross-plane conductance of SAMs formed from anthracene-based molecules with four different combinations of anchors are measured to differ by a factor of approximately 3 in agreement with theoretical predictions. We also demonstrate that the Seebeck coefficient of such films can be boosted by more than an order of magnitude by an appropriate choice of anchor groups and that both positive and negative Seebeck coefficients can be realised. This demonstration that the thermoelectric properties of SAMs are controlled by their anchor groups represents a critical step towards functional ultra-thin-film devices for future molecular-scale electronics.

  • Conference paper
    Long NJ, 2020,

    Inorganic chemistry for PET radiolabelling: Ga-68- and F-18-based probes for mitochondria imaging

    , Publisher: WILEY, Pages: 359-359, ISSN: 0362-4803

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