Publications

Journal article

Boddy AJ, Sahay AK, Rivers EL, White AJP, Spivey A, Bull Jet al., 2024,

Enantioselective phase transfer catalyzed synthesis of spirocyclic azetidine oxindoles

, Organic Letters, Vol: 26, Pages: 2079-2084, ISSN: 1523-7052

Spiro-3,2’-azetidine oxindoles combine two independently important pharmacophores in an understudied spirocyclic motif that is attractive for medicinal chemistry. Here, the enantioselective synthesis of these structures is achieved in ers of up to 2:98 through intramolecular C–C bond formation, involving activation of the substrate with a novel SF5-containing chiral cation phase transfer (PT) catalyst. The products are readily elaborated/deprotected to afford medicinally relevant enantioen-riched compounds. Control experiments suggest an interfacial PT mechanism, whereby catalytic asymmetric induction is achieved through activation of the chloride leaving group.

Journal article

Piletsky S, Baidyuk E, Piletska EV, Lezina L, Shevchenko K, Jones DJL, Cao TH, Singh R, Spivey A, Aboagye E, Piletsky S, Barlev Net al., 2023,

Modulation of EGFR activity by molecularly imprinted polymer nanoparticles targeting intracellular epitopes

, Nano Letters: a journal dedicated to nanoscience and nanotechnology, Vol: 23, Pages: 9677-9682, ISSN: 1530-6984

In recent years, molecularly imprinted polymer nanoparticles (nanoMIPs) have proven to be an attractive alternative to antibodies in diagnostic and therapeutic applications. However, several key questions remain: how suitable are intracellular epitopes as targets for nanoMIP binding? And to what extent can protein function be modulated via targeting specific epitopes? To investigate this, three extracellular and three intracellular epitopes of epidermal growth factor receptor (EGFR) were used as templates for the synthesis of nanoMIPs which were then used to treat cancer cells with different expression levels of EGFR. It was observed that nanoMIPs imprinted with epitopes from the intracellular kinase domain and the extracellular ligand binding domain of EGFR caused cells to form large foci of EGFR sequestered away from the cell surface, caused a reduction in autophosphorylation, and demonstrated effects on cell viability. Collectively, this suggests that intracellular domain-targeting nanoMIPs can be a potential new tool for cancer therapy.

Journal article

Dai C, Spivey AC, 2023,

Celastraceae sesquiterpene pyridyl ligands

, Organic Chemistry Frontiers, Vol: 10, Pages: 5296-5308, ISSN: 2052-4129

Celastraceae plant extracts have been widely used as traditional medicines and insecticides in China and South America. More recently, the extracts from Celastraceae plants have been studied at the molecular level and many of the interesting medicinal and agrochemical properties can be attributed to a large class of sesquiterpene alkaloids found in these extracts. These are generally based on highly oxygenated dihydroagarofuran cores with pyridyl diacid macrodilactone bridging ligands. Whereas previous reviews have focused on the dihydroagarofuran cores, in this article, the history, structure, and syntheses of the macrodilactone bridging ligands are reviewed.

Journal article

Greenaway RLL, Jelfs KEE, Spivey ACC, Yaliraki SNNet al., 2023,

From alchemist to AI chemist

, NATURE REVIEWS CHEMISTRY, Vol: 7, Pages: 527-528

Journal article

Swan AH, Schindler RFR, Savarese M, Mayer I, Rinne S, Bleser F, Schaenzer A, Hahn A, Sabatelli M, Perna F, Chapman K, Pfuhl M, Spivey AC, Decher N, Udd B, Tasca G, Brand Tet al., 2023,

Correction: Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking

, Acta Neuropathologica Communications, Vol: 11, ISSN: 2051-5960

Journal article

Swan A, Schindler R, Savarese M, Mayer I, Rinné S, Bleser F, Schänzer A, Hahn A, Sabatelli M, Perna F, Kathryn C, Pfuhl M, Spivey AC, Decher N, Udd B, Brand T, Tasca Get al., 2023,

Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking

, Acta Neuropathologica Communications, Vol: 11, Pages: 1-25, ISSN: 2051-5960

The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance (BVES) also known as POPDC1 and POPDC2 have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membranetrafficking of both POPDC isoforms. Biopsy material of patients carrying mutations in BVES were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein-protein interaction. Patients carrying a novel homozygous variant, BVES (c.547G>T, p.V183F) displayed only askeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. In contrast, variants such as BVES p.Q153X or POPDC2 p.W188X were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1-POPDC2 complex. Mutations in POPDC proteins that cause an impairment in membrane localisation affect POPDC complex formation while mutations which leave protein-protein interaction intact likely affect some other essential function of POPDC proteins.

Journal article

Piletsky S, Kassem S, Yesilkaya H, Gazioglu O, Habtom M, Canfarotta F, Piletska E, Spivey A, Aboagye E, Piletsky Set al., 2022,

Assessing the in vivo biocompatibility of molecularly imprinted polymer nanoparticles

, Polymers, Vol: 14, Pages: 1-15, ISSN: 2073-4360

Molecularly imprinted polymer nanoparticles (nanoMIPs) are high affinity synthetic receptors which show promise as imaging and therapeutic agents. Comprehensive analysis of the in vivo behaviour of nanoMIPs must be performed before they can be considered for clinical applications. This work reports the solid-phase synthesis of nanoMIPs and an investigation of their biodistribution, clearance and cytotoxicity in a rat model following both intravenous and oral administration. These nanoMIPs were found in each harvested tissue type, including brain tissue, implying their ability to cross the blood brain barrier. The nanoMIPs were cleared from the body via both faeces and urine. Furthermore, we describe an immunogenicity study in mice, demonstrating that nanoMIPs specific for a cell surface protein showed moderate adjuvant properties, whilst those imprinted for a scrambled peptide showed no such behaviour. Given their ability to access all tissue types and their relatively low cytotoxicity, these results pave the way for in vivo applications of nanoMIPs.

Working paper

Swan AH, Schindler RFR, Savarese M, Mayer I, Rinné S, Bleser F, Schänzer A, Hahn A, Sabatelli M, Perna F, Chapman K, Pfuhl M, Spivey AC, Decher N, Udd B, Tasca G, Brand Tet al., 2022,

Differential Effects of Mutations of Popeye Domain Containing Proteins on Heteromeric Interaction and Membrane Trafficking

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Popeye domain containing (POPDC) genes encode sarcolemma-localised cAMP effector proteins. Mutations in<jats:italic>BVES (POPDC1)</jats:italic>and<jats:italic>POPDC2</jats:italic>have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Biopsy material of patients carrying mutations in<jats:italic>BVES</jats:italic>were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein interaction.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Patients carrying a novel homozygous variant,<jats:italic>BVES</jats:italic>(c.547G>T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. This is in contrast to variants such as<jats:italic>BVES</jats:italic>p.Q153X or<jats:italic>POPDC2</jats:italic>p.W188X, which were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1-POPDC2 complex.</jats:p></jats:sec><jats:sec><jats:title>Interpretat

Journal article

Piletsky S, Garcia Cruz A, Piletska E, Piletsky S, Aboagye E, Spivey Aet al., 2022,

Iodo silanes as superior substrates for the solid phase synthesis of molecularly imprinted polymer nanoparticles

, Polymers, Vol: 14, Pages: 1-8, ISSN: 2073-4360

Current state-of-the-art techniques for the solid phase synthesis of molecularly imprinted polymer (MIP) nanoparticles typically rely on amino silanes for the immobilisation of template molecules prior to polymerisation. An investigation into commonly used amino silanes identified a number of problematic side reactions which negatively affect the purity and affinity of these polymers. Iodo silanes are presented as a superior alternative in a case study describing the synthesis of MIPs against epitopes of a common cancer biomarker, epidermal growth factor receptor (EGFR). The proposed iodo silane outperformed the amino silane by all metrics tested, showing high purity and specificity, and nanomolar affinity for the target peptide.

Journal article

Nielsen CD-T, Linfoot JD, Williams AF, Spivey ACet al., 2022,

Recent progress in asymmetric synergistic catalysis - the judicious combination of selected chiral aminocatalysts with achiral metal catalysts

, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 20, Pages: 2764-2778, ISSN: 1477-0520

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Citations: 10

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

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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

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Spivey AC, 2020,

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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><div><p>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 <i>via</i> alternative methods. Intermoleculartransfer hydrogenation andhydrothiolation are also demonstrated. </p></div></jats:p>

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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>

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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.

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

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