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Journal articleRadzikowski JL, Delmas L, Cohen E, et al., 2024,
Chemical Kitchen─A transdisciplinary introduction to a laboratory practice that rebalances students’ self-efficacy
, Journal of Chemical Education, Vol: 101, Pages: 5353-5360, ISSN: 0021-9584Transition from high school to higher education poses a significant challenge for students, particularly in chemistry, where students’ prior laboratory experience is varied. Traditional laboratory education, focusing on chemical knowledge, scientific methodology, and practical skills, does not focus on the development of translational skills and establishing a proper level of self-efficacy, critical for students’ success as future scientists. To address this problem, we developed the Chemical Kitchen, a transdisciplinary simulation utilizing the parallels between professional gastronomy and chemistry laboratory practices. By engaging students in creative food experiments that mimic chemistry experiments, the course aims to enhance practical skills in a less intimidating environment. We evaluated the impact of the Chemical Kitchen on students’ self-efficacy through pre- and postcourse surveys. We found a significant adjustment in students’ self-efficacy: those with initially lower self-efficacy experienced increases, while those with initially higher self-efficacy saw decreases, showing a “leveling of the playing field” among first-year chemistry students. Qualitative feedback highlighted the course’s success in providing a fun, engaging, and meaningful learning experience, underscoring the importance of innovative teaching methods in enhancing practical skills and confidence. This study demonstrates the effectiveness of the Chemical Kitchen in establishing students’ self-efficacy and practical and transferable skills, offering a novel approach to laboratory education that could be beneficial across various scientific disciplines. Future research is encouraged to explore the long-term effects of such interventions on students’ engagement with science and their overall development as learners.
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Journal articleBoddy AJ, Sahay AK, Rivers EL, et al., 2024,
Enantioselective phase transfer catalyzed synthesis of spirocyclic azetidine oxindoles
, Organic Letters, Vol: 26, Pages: 2079-2084, ISSN: 1523-7052Spiro-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.
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Journal articlePiletsky S, Baidyuk E, Piletska EV, et 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: 1530-6984In 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.
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Journal articleDai C, Spivey AC, 2023,
Celastraceae sesquiterpene pyridyl ligands
, Organic Chemistry Frontiers, Vol: 10, Pages: 5296-5308, ISSN: 2052-4129Celastraceae 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.
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Journal articleGreenaway RLL, Jelfs KEE, Spivey ACC, et al., 2023,
From alchemist to AI chemist
, NATURE REVIEWS CHEMISTRY, Vol: 7, Pages: 527-528 -
Journal articleSwan AH, Schindler RFR, Savarese M, et 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 articleSwan A, Schindler R, Savarese M, et al., 2023,
Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking
, Acta Neuropathologica Communications, Vol: 11, Pages: 1-25, ISSN: 2051-5960The 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.
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Journal articlePiletsky S, Kassem S, Yesilkaya H, et al., 2022,
Assessing the in vivo biocompatibility of molecularly imprinted polymer nanoparticles
, Polymers, Vol: 14, Pages: 1-15, ISSN: 2073-4360Molecularly 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.
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Working paperSwan AH, Schindler RFR, Savarese M, et 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
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Journal articlePiletsky S, Garcia Cruz A, Piletska E, et al., 2022,
Iodo silanes as superior substrates for the solid phase synthesis of molecularly imprinted polymer nanoparticles
, Polymers, Vol: 14, Pages: 1-8, ISSN: 2073-4360Current 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.
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Journal articleNielsen CD-T, Linfoot JD, Williams AF, et 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- Author Web Link
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- Citations: 10
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Journal articlePiletsky S, Piletska E, Poblocka M, et 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: 1748-0132Proteomic 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.
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Journal articleLinfoot 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 articleAlamillo-Ferrer C, Nielsen CD-T, Salzano A, et 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 articleRadzikowski J, Delmas L, Spivey A, et al., 2021,
The Chemical Kitchen: Towards Remote Delivery of an Interdisciplinary Practical Course
, Journal of Chemical Education, ISSN: 0021-9584 -
Journal articleCesarec S, Robson JA, Carroll LS, et al., 2020,
Direct incorporation of [18F] into Aliphatic Systems: a promising Mn-catalysed labelling technique for PET imaging
, Current Radiopharmaceuticals, Vol: 13, ISSN: 1874-4710BACKGROUND: 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.
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Journal articleWilliams AF, White AJP, Spivey AC, et 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 -
BookSpivey AC, 2020,
Preface
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Journal articleAubert S, Bezagu M, Spivey AC, et al., 2019,
Spatial and temporal control of chemical processes
, NATURE REVIEWS CHEMISTRY, Vol: 3, Pages: 706-722 -
Journal articleNielsen CD-T, White AJP, Sale D, et 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 articleNielsen C, White AJP, Sale D, et 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 articleNielsen C, White A, Sale D, et 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 articleCryer AM, Chan C, Eftychidou A, et 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: 1944-8244Gold 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.
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Journal articleFerris T, Carroll L, Mease RC, et 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: 0040-4039Herein, 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.
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Journal articleBoddy AJ, Cordier C, Goldberg K, et 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: 1523-7052The 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.
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Journal articleBoddy A, Affron D, Cordier C, et 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: 1521-3757Methods 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.
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Journal articleNielsen CD-T, Mooij WJ, Sale D, et 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: 2041-6520Herein 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.
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Journal articleKneebone 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 articleKneebone 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 articleNielsen 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: 0039-7881Herein 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.
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Contact details
Email: a.c.spivey@imperial.ac.uk
Skype: alan.spivey
Tel & Fax: +44 (0)20 75945841
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