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  • Journal article
    Piletsky S, Piletska E, Poblocka M, Macip S, Jones D, Braga M, Cao T, Singh R, Spivey A, Aboagye E, Piletsky Set al., 2021,

    Snapshot imprinting: Rapid identification of cancer cell surface proteins and epitopes using molecularly imprinted polymers

    , Nano Today: an international rapid reviews journal, Vol: 41, Pages: 1-8, ISSN: 1748-0132

    Proteomic mapping of cell surfaces is an invaluable tool for drug development and clinical diagnostics. This work describes a new ‘snapshot imprinting’ method designed to obtain proteomic maps of cell surfaces, with the aim of identifying cell surface markers and epitopes for diagnostic and therapeutic applications. The analysis of two cancer cell lines, HN5 and MDA-MB-468, is described herein as a proof of concept, along with the selective targeting of three identified epitopes of epidermal growth factor receptor using molecularly imprinted polymer nanoparticles. 438 proteins were identified using this technique, with 283 considered to be transmembrane or extracellular proteins. The major advantage of the molecular imprinting approach developed here is the ability to analyse cell surface proteins without tedious fractionation, affinity separation or labelling. We believe that this system of protein analysis may provide a basic molecular diagnostics toolbox for precise, personalised treatment of cancer and other diseases.

  • Journal article
    Linfoot JD, Williams AF, Spivey AC, 2021,

    MIDA-directed meta-selective C−H functionalizations

    , Trends in Chemistry, Vol: 3, Pages: 512-513, ISSN: 2589-5974
  • Journal article
    Alamillo-Ferrer C, Nielsen CD-T, Salzano A, Companyo X, Di Sanza R, Spivey AC, Rzepa HS, Bures Jet al., 2021,

    Understanding the Diastereopreference of Intermediates in Aminocatalysis: Application to the Chiral Resolution of Lactols

    , JOURNAL OF ORGANIC CHEMISTRY, Vol: 86, Pages: 4326-4335, ISSN: 0022-3263
  • Journal article
    Radzikowski J, Delmas L, Spivey A, Youssef J, Kneebone Ret al., 2021,

    The Chemical Kitchen: Towards Remote Delivery of an Interdisciplinary Practical Course

    , Journal of Chemical Education, ISSN: 0021-9584
  • Journal article
    Cesarec S, Robson JA, Carroll LS, Aboagye EO, Spivey ACet al., 2020,

    Direct incorporation of [18F] into Aliphatic Systems: a promising Mn-catalysed labelling technique for PET imaging

    , Current Radiopharmaceuticals, Vol: 13, ISSN: 1874-4710

    BACKGROUND: One of the challenges in positron emission tomography (PET) is labellingcomplex aliphatic molecules. OBJECTIVE: This study aimed to develop a method of metal-catalysed radiofluorination that is site-selectiveand works in moderate to good yields under facile conditions. METHODS: Herein, we report on the optimisation of an aliphatic C-H to C-18F bond transformationcatalysed by a Mn(porphyrin) complex. RESULTS: The successful oxidation of 11 aliphatic molecules, including progesterone, is reported.Radiochemical Incorporations (RCIs) up to 69% were achieved within 60 min without the need forpre-activation or special equipment. CONCLUSION: The method features mild conditions (60 °C) and promises to constitute a valuable approachto labelling of biomolecules and drug substances.

  • Journal article
    Williams AF, White AJP, Spivey AC, Cordier CJet al., 2020,

    meta-Selective C-H functionalisation of aryl boronic acids directed by a MIDA-derived boronate ester

    , CHEMICAL SCIENCE, Vol: 11, Pages: 3301-3306, ISSN: 2041-6520
  • Journal article
    Aubert S, Bezagu M, Spivey AC, Arseniyadis Set al., 2019,

    Spatial and temporal control of chemical processes

    , NATURE REVIEWS CHEMISTRY, Vol: 3, Pages: 706-722
  • Journal article
    Nielsen CD-T, White AJP, Sale D, Bures J, Spivey ACet al., 2019,

    Hydroarylation of Alkenes by Protonation/Friedel-Crafts Trapping: HFIP-Mediated Access to Per-aryl Quaternary Stereocenters

    , JOURNAL OF ORGANIC CHEMISTRY, Vol: 84, Pages: 14965-14973, ISSN: 0022-3263
  • Journal article
    Nielsen C, White AJP, Sale D, Bures J, Spivey Aet al., 2019,

    Hydroarylation of Alkenes by protonation/Friedel-Crafts Trapping – HFIP-Mediated Access to Per-Aryl Quaternary Stereocentres

    , ChemRxiv

    <jats:p>&lt;div&gt;&lt;p&gt;Upon treatment with a combination of HFIPand a strong Brønsted acid, alkenes behave as Brønsted bases and protonate to givecarbocations which can be trapped by electron rich arenes. The reaction constitutesa Friedel-Crafts (FC) hydroarylation which proceeds with Markovnikovselectivity and is orthogonal to traditional metal catalyzed processes. Theproducts contain polyarylated quaternary carbon atoms which are difficult toobtain &lt;i&gt;via&lt;/i&gt; alternative methods. Intermoleculartransfer hydrogenation andhydrothiolation are also demonstrated. &lt;/p&gt;&lt;/div&gt;</jats:p>

  • Journal article
    Nielsen C, White A, Sale D, Bures J, Spivey Aet al., 2019,

    Hydroarylation of Alkenes by protonation/Friedel-Crafts Trapping – HFIP-Mediated Access to Per-Aryl Quaternary Stereocentres

    , ChemRxiv

    <div> <p>Upon treatment with a combination of HFIP and a strong Brønsted acid, alkenes behave as Brønsted bases and protonate to give carbocations which can be trapped by electron rich arenes. The reaction constitutes a Friedel-Crafts (FC) hydroarylation which proceeds with Markovnikov selectivity and is orthogonal to traditional metal catalyzed processes. The products contain polyarylated quaternary carbon atoms which are difficult to obtain <i>via</i> alternative methods. Intermolecular transfer hydrogenation and hydrothiolation are also demonstrated. </p> </div>

  • Journal article
    Cryer AM, Chan C, Eftychidou A, Maksoudian C, Mahesh M, Tetley TD, Spivey AC, Thorley AJet al., 2019,

    Tyrosine kinase inhibitor gold nanoconjugates for the treatment of non-small cell lung cancer

    , ACS Applied Materials and Interfaces, Vol: 11, Pages: 16336-16346, ISSN: 1944-8244

    Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide functionalized lipoic acid using copper catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less pro-inflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of non-traditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.

  • Journal article
    Ferris T, Carroll L, Mease RC, Spivey AC, Aboagye EOet al., 2019,

    Iodination of terminal alkynes using KI/CuSO4 – A facile method with potential for radio-iodination

    , Tetrahedron Letters, Vol: 60, Pages: 936-939, ISSN: 0040-4039

    Herein, we report an efficient new method for the iodination of terminal alkynes using stoichiometric KI and CuSO4 in a mix of acetonitrile and acetate buffer that holds promise for further development into a method for radio-iodination.

  • Journal article
    Boddy AJ, Cordier C, Goldberg K, Madin A, Spivey AC, Bull Jet al., 2019,

    Acid-mediated ring-expansion of 2,2-disubstituted azetidine carbamates to 6,6-disubstituted 1,3-oxazinan-2-ones

    , Organic Letters, Vol: 21, Pages: 1818-1822, ISSN: 1523-7052

    The ring expansion of 2-ester-2-aryl-azetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives, and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporated. The combina-tion of this ring expansion in a 3-step N–H insertion/cyclization/expansion (NICE) sequence is applied to directly access medicinally relevant scaffolds from acyclic precursors.

  • Journal article
    Boddy A, Affron D, Cordier C, Rivers E, Spivey A, Bull Jet al., 2019,

    Rapid assembly of saturated nitrogen heterocycles in one-pot: Diazo–heterocycle ‘stitching’ by N–H insertion and cyclization

    , Angewandte Chemie International Edition, Vol: 58, Pages: 1458-1462, ISSN: 1521-3757

    Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, piperidines and azepanes bearing ester and diverse aryl substituents. A one-pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m-haloamines (m = 2 to 5) to rapidly assemble 4-, 5-, 6- and 7-membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including with diazo compounds derived from biologically active compounds. The products can be functionalized to afford alpha,alpha-disubstituted amino acids and applied to fragment synthesis.

  • Journal article
    Nielsen CD-T, Mooij WJ, Sale D, Rzepa HS, Bures J, Spivey ACet al., 2019,

    Reversibility and reactivity in an acid catalyzed cyclocondensation to give furanochromanes - a reaction at the "oxonium-Prins' vs. "ortho-quinone methide cycloaddition' mechanistic nexus

    , Chemical Science, Vol: 10, Pages: 406-412, ISSN: 2041-6520

    Herein we report a combined experimental and computational investigation of the acid catalyzed cyclocondensation reaction between styrenyl homoallylic alcohols and salicylaldehyde to form furanochromanes. We disclose a previously unreported isomerisation of the ‘unnatural’ trans-fused products to the diastereomeric ‘natural’ cis-fused congeners. Notwithstanding the appeal of assuming this corresponds to endo to exo isomerisation of Diels–Alder (D–A) adducts via concerted retro-cycloaddition/cycloaddition reactions of an in situ generated ortho-quinone methide with the styrenyl alkene, our combined Hammett/DFT study reveals a stepwise Prins-like process via discrete benzylic carbocation intermediates for all but the most electron deficient styrenes. As these reactions fortuitously lie at the intersection of these two mechanistic manifolds, it allows us to propose an experimentally determined indicative ρ+ value of ca. −3 as marking this nexus between a stepwise Prins-type pathway and a concerted cycloaddition reaction. This value should prove useful for categorising other reactions formally involving ‘ortho-quinomethides’, without the need for the extensive computation performed here. Logical optimisation of the reaction based upon the mechanistic insight led to the use of HFIP as an additive which enables exclusive formation of ‘natural’ cis-fused products with a ∼100-fold reaction rate increase and improved scope.

  • Journal article
    Kneebone R, Schlegel C, Spivey A, 2018,

    Science in hand: how art and craft can boost reproducibility

    , Nature, Vol: 564, Pages: 188-189, ISSN: 0028-0836
  • Journal article
    Kneebone R, Schlegel C, Spivey A, 2018,

    Science in hand: how art and craft can boost reproducibility

    , Nature, Vol: 564, Pages: 188-189, ISSN: 0028-0836
  • Journal article
    Nielsen CD-T, Abas H, Spivey AC, 2018,

    Stereoselective reactions of ortho-quinone methide and ortho-quinone methide imines and their utility in natural product synthesis

    , SYNTHESIS, Vol: 50, Pages: 4008-4018, ISSN: 0039-7881

    Herein presented is a review of the reactivity and synthetic utility of ortho-quinone methides and ortho-quinone methide imines. These versatile intermediates have received significant attention in the literature and new methods for their preparation and reaction as well as recent applications in total synthesis are discussed.

  • Journal article
    Griffiths K, Tsipis AC, Kumar P, Townrow OPE, Abdul-Sada A, Akien GR, Baldansuren A, Spivey AC, Kostakis GEet al., 2017,

    3d/4f Coordination Clusters as Cooperative Catalysts for Highly Diastereoselective Michael Addition Reactions

    , INORGANIC CHEMISTRY, Vol: 56, Pages: 9563-9573, ISSN: 0020-1669

    Michael addition (MA) is one of the most well studied chemical transformation in synthetic chemistry. Here, we report the synthesis and crystal structures of a library of 3d/4f coordination clusters (CCs) formulated as [ZnII2YIII2L4(solv)X(Z)Y] and study their catalytic properties toward the MA of nitrostyrenes with barbituric acid derivatives. Each CC presents two borderline hard/soft Lewis acidic ZnII centers and two hard Lewis acidic YIII centers in a defect dicubane topology that brings the two different metals into a proximity of ∼3.3 Å. Density functional theory computational studies suggest that these tetrametallic CCs dissociate in solution to give two catalytically active dimers, each containing one 3d and one 4f metal that act cooperatively. The mechanism of catalysis has been corroborated via NMR, electron paramagnetic resonance, and UV–vis. The present work demonstrates for the first time the successful use of 3d/4f CCs as efficient and high diastereoselective catalysts in MA reactions.

  • Journal article
    Abas H, Linsdall SM, Mamboury M, Rzepa HS, Spivey ACet al., 2017,

    Total Synthesis of (+)-Lophirone H and Its pentamethyl ether utilizing an oxonium-prins cyclization

    , Organic Letters, Vol: 19, Pages: 2486-2489, ISSN: 1523-7052

    The first total synthesis of (+)-lophirone H (1) and its pentamethyl ether 29, featuring an oxonium–Prins cyclization/benzylic cation trapping reaction, is described.

  • Journal article
    Murray JI, Flodén NJ, Bauer A, Fessner ND, Dunklemann DL, Bob-Egbe O, Rzepa HS, Bürgi T, Richardson J, Spivey ACet al., 2017,

    Kinetic Resolution of 2-Substituted Indolines by N -Sulfonylation using an Atropisomeric 4-DMAP- N -oxide Organocatalyst

    , Angewandte Chemie, Vol: 129, Pages: 5854-5858, ISSN: 0044-8249

    The first catalytic kinetic resolution by N‐sulfonylation is described. 2‐Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4‐dimethylaminopyridine‐N‐oxide (4‐DMAP‐N‐oxide) organocatalyst. Use of 2‐isopropyl‐4‐nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

  • Journal article
    Murray JI, Floden NJ, Bauer A, Fessner ND, Dunklemann DL, Bob-Egbe O, Rzepa HS, Burgi T, Richardson J, Spivey ACet al., 2017,

    Kinetic resolution of 2-substituted indolines by N-sulfonylation using an atropisomeric 4-DMAP-N-oxide organocatalyst

    , Angewandte Chemie International Edition, Vol: 56, Pages: 5760-5764, ISSN: 1433-7851

    The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

  • Journal article
    Frampton CS, Murray JI, Spivey AC, 2017,

    Crystal structure of 1-methylimidazole 3-oxide monohydrate.

    , Acta Crystallographica Section E: Crystallographic Communications, Vol: 73, Pages: 372-374, ISSN: 2056-9890

    1-Methylimidazole 3-N-oxide (NMI-O) crystallizes as a monohydrate, C4H6N2O·H2O, in the monoclinic space group P21 with Z' = 2 (mol-ecules A and B). The imidazole rings display a planar geometry (r.m.s. deviations = 0.0008 and 0.0002 Å) and are linked in the crystal structure into infinite zigzag strands of ⋯NMI-O(A)⋯OH2⋯NMI-O(B)⋯OH2⋯ units by O-H⋯O hydrogen bonds. These chains propagate along the b-axis direction of the unit cell.

  • Journal article
    Bodero O, Spivey AC, 2016,

    An expedient synthesis of 2-aryl-1,4-benzoxazin-3-ones via tandem Anionic cyclisation/alkylation reactions of N-Boc-O-benzyl-2-aminophenols

    , Synlett, Vol: 27, ISSN: 0936-5214

    A one-pot, tandem anionic cyclization/alkylation reaction of N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the tert-butoxide liberated in the cyclisation step facilitates the benzylic deprotonation necessary for the subsequent alkylation. The reaction gives expedient access to a range of substitution patterns in 1,4-benzoxazin-3-ones of potential biological relevance.

  • Journal article
    Murray JI, Spivey AC, 2016,

    Preparation of 1-Methylimidazole- N-oxide (NMI-O)

    , ORGANIC SYNTHESES, Vol: 93, Pages: 331-+, ISSN: 0078-6209
  • Journal article
    Abas H, Frampton CS, Spivey AC, 2016,

    Diels-Alder Reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene

    , Journal of Organic Chemistry, Vol: 81, Pages: 9947-9956, ISSN: 1520-6904

    Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition.

  • Book chapter
    Murray JI, Heckenast Z, Spivey AC, 2016,

    Chiral Lewis Base Activation of Acyl and Related Donors in Enantioselective Transformations (n → π*)

    , Lewis Base Catalysis in Organic Synthesis, Pages: 457-526, ISBN: 9783527336180

    The role of Lewis bases in acylation reactions has been studied from both synthetic and mechanistic standpoints with a particular recent focus on enantioselective variants mediated by single enantiomer chiral Lewis bases deployed substoichiometrically. The modern-era of research into asymmetric enantioselective nucleophile-catalyzed acyl transfer using designed nucleophiles was initiated in the mid-1990s by the groups of Vedejs and Fu. This group developed chiral ferro-cenyl 4-dialkylaminopyridine derivatives first for the kinetic resolution (KR) of sec-alcohols and for an array of other transformations. Since the 1980s, the synthetic potential of enantioselective acylation has been well established in the context of fine chemical synthesis as a result of the development of biocatalytic processes that rely on hydrolytic enzymes. Cognizant that both bases and nucleophiles catalyze the acylation of alcohols using anhydrides and that alkyl phosphines in particular display weak basicity and strong nucleophilicity, Vedejs and Diver published a study of the utility of phosphines as acyl transfer catalysts.

  • Journal article
    Almond-Thynne J, Blakemore DC, Pryde DC, Spivey ACet al., 2016,

    Site-selective Suzuki-Miyaura coupling of heteroaryl halides - understanding the trends for pharmaceutically important classes

    , Chemical Science, Vol: 8, Pages: 40-62, ISSN: 2041-6539

    Suzuki–Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found.

  • Conference paper
    Spivey A, 2016,

    Lewis-base catalysis of asymmetric acylation, sulfonylation, and phosphorylation processes

    , Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Murray JI, Spivey AC, 2015,

    Amines vs. N-Oxides as Organocatalysts for Acylation, Sulfonylation and Silylation of Alcohols: 1-Methylimidazole N-Oxide as an Efficient Catalyst for Silylation of Tertiary Alcohols

    , ADVANCED SYNTHESIS & CATALYSIS, Vol: 357, Pages: 3825-3830, ISSN: 1615-4150

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