Abstracts From the 29th International Isotope Society UK Meeting 17th November 2023

IF 0.9 4区医学 Q4 BIOCHEMICAL RESEARCH METHODS

Journal of labelled compounds & radiopharmaceuticals Pub Date : 2024-08-21 DOI:10.1002/jlcr.4115

{"title":"Abstracts From the 29th International Isotope Society UK Meeting 17th November 2023","authors":"","doi":"10.1002/jlcr.4115","DOIUrl":null,"url":null,"abstract":"Matthew J. Fuchter1Department of Chemistry Imperial College LondonPhotoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications, from molecular motors, memory, and manipulators to solar thermal storage. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one or both of the aryl rings from the conventional azobenzene class has been replaced with a heteroaromatic ring. This talk will give an overview of our work in this area, initially focusing on our discovery of the arylazopyrazoles [1], which offer quantitative photoswitching and high thermal stability of the Z isomer. It will go on to describe our elucidation of structure–property relationships for a wide array of comparable azoheteroaryl photoswitches [2, 3]. Through this, we have identified compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics, all through tuning of the heteraromatic ring.Given the large tunability of their properties, the predictive nature of their performance, and the other potential functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potential in a wide range of optically addressable applications. This talk will particularly focus on the promise of such agents in photopharmacology: light-addressable drugs [4–6].References1. \n C. E. Weston, R. D. Richardson, P. R. Haycock, A. J. P. White, and M. J. Fuchter, “ Arylazopyrazoles: Azoheteroarene Photoswitches Offering Quantitative Isomerization and Long Thermal Half-Lives,”Journal of the American Chemical Society 136, (2014): 11878–11881.2. \n J. Calbo, C. E. Weston, A. J. P. White, H. Rzepa, J. Contreras-García, and M. J. Fuchter, “ Tuning Azoheteroarene Photoswitch Performance Through Heteroaryl Design,” Journal of the American Chemical Society 139, (2017): 1261–1274.3. \n A. Gonzalez, M. Odaybat, M. Le, et al., “ Photocontrolled Energy Storage in Azobispyrazoles With Exceptionally Large Light Penetration Depths,” Journal of the American Chemical Society 144, (2022): 19430–19436.4. \n C. E. Weston, A. Kraemer, F. Colin, et al., “ Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors,” ACS Infectious Diseases 3, (2017): 152–161.5. \n P. Y. Lam, A. R. Thawani, E. Balderas, et al., “ TRPswitch—A Step-Function Chemo-Optogenetic Ligand for the Vertebrate TRPA1 Channel,” Journal of the American Chemical Society 142, (2020): 17457–17468.6. \n M. J. Fuchter, “ On the Promise of Photopharmacology Using Photoswitches: A Medicinal Chemist’s Perspective,” Journal of Medicinal Chemistry 63, (2020): 11436–11447.Alex CresswellDepartment of Chemistry, University of Bath\n <!--EMPTY>We have recently found that primary aliphatic amines without N-protection can be employed directly in photoredox catalysis to form new C–C bonds α- to nitrogen, using a variety of radicophiles as coupling partners [1–4]. This is a key advance for amine synthesis, providing a highly simplifying disconnection for α-tertiary amines and saturated azacycles, including spirocycles. This short talk will summarise some of our recent results in this area, as well as touching upon some currently unpublished results.References1. \n H. E. Askey, J. D. Grayson, J. D. Tibbetts, et al., “ Photocatalytic Hydroaminoalkylation of Styrenes With Unprotected Primary Alkylamines,” Journal of the American Chemical Society 143, (2021): 15936–15945.2. \n J. D. Grayson, and A. J. Cresswell, “ γ-Amino Phosphonates via the Photocatalytic α-C–H Alkylation of Primary Amines,” Tetrahedron 81, (2021): 131896.3. \n A. S. H. Ryder, W. B. Cunningham, G. Ballantyne, et al. “ Photocatalytic α-Tertiary Amine Synthesis via C−H Alkylation of Unmasked Primary Amines,” Angewandte Chemie, International Edition 59, (2020): 14986–14991.4. \n Q. Cao, J. D. Tibbetts, A. P. Smalley, and A. J. Cresswell, “ Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines From Primary Alkylamines,” Communications Chemistry, 6, (2023): 215.Kim S. Mühlfenzl1,2Vitus J. Enemærke2Sahil Gahlawat3,4Peter I. Golbækdal2Nikoline Munksgaard Ottosen2Karoline T. Neumann2Kathrin H. Hopmann3Per-Ola Norrby5Charles S. Elmore1Troels Skrydstrup21Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden2Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark3Department of Chemistry, UiT The Arctic University of Norway, Tromsø, Norway4Hylleraas Center for Quantum Molecular Sciences, UiT The Arctic University of Norway, Tromsø, Norway5Data Science & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, SwedenA versatile and efficient nickel-catalyzed decarboxylative carbonylative cross-coupling of readily formed redox-activated alkyl tetrachlorophthalimide esters and aryl boronic acids to form aryl-alkyl ketones is presented. The methodology can be easily tuned to incorporate carbon isotope labels by using labeled SilaCOgen or COgen as CO-surrogates, allowing late-stage isotope labeling of drug candidates. The methodology exhibits a broad substrate scope under mild conditions and is expanded to the synthesis of pharmacologically relevant compounds and their 13/14C-enriched isotopologues. Computational and experimental investigations were performed and support the key steps of the proposed catalytic cycle, including the involvement of carbon-centered radicals formed via a nickel-induced outer-sphere decarboxylative fragmentation of the redox-active ester.Nick SummerhillPharmaronKetamine is an injectable dissociative-hypnotic derived from phencyclidine in 1962 in pursuit of a safer anaesthetic with fewer hallucinogenic effects. It was initially approved for human and veterinary use to induce and maintain anaesthesia [1]. In recent years, it has attracted additional attention due to its utility as an adjunctive, opioid-sparing analgesic [2] and its rapid and sustained antidepressant effects, with an intranasal formulation of Esketamine (the S-enantiomer of ketamine) receiving approval for use in treatment-resistant depression and depressed patients with acute suicidal ideation or behaviour [3]. In addition to these medical uses, ketamine is commonly misused because of its ability to induce an altered state of consciousness [4].\n <!--EMPTY>This presentation will outline a synthesis of carbon-14 labelled ketamine utilising the key intermediate [14C] 2-chlorophenyl cyclopentyl ketone (1). Various approaches to the key intermediate will be discussed, concluding with a robust and high yielding synthesis.\n <!--EMPTY>References1. \n M. A. Peltoniemi, N. M. Hagelberg, K. T. Olkkola, and T. I. Saari, “ Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy,” Clinical Pharmacokinetics 55, (2016): 1059–1077.2. \n C. Culp, H. K. Kim, and Abdi, S., “ Ketamine Use for Cancer and Chronic Pain Management,” Frontiers in Pharmacology 11, (2020): 599721.3. \n E. P. McMullen, Y. Lee, O. Lipsitz, et al., “ Strategies to Prolong Ketamine’s Efficacy in Adults With Treatment-Resistant Depression,” Advances in Therapy 38, (2021): 2795–2820.4. \n P. Zanos, R. Moaddel, P. J. Morris, et al., “ Ketamine and Ketamine Metabolite Pharmacology: Insights Into Therapeutic Mechanisms,” Pharmacological Reviews 70, (2018): 621–660.Roly ArmstrongNewcastle UniversityThis talk will discuss the development of transition metal-catalyzed alkylation reactions of twisted pentamethylphenyl ketones. The focus will be upon how this concept can be used for the stereoselective synthesis of cyclic scaffolds through formation of multiple C–C bonds. These reactions can be augmented by an appropriate ligand to enable the development of catalytic asymmetric variants, as well as acceptorless dehydrogenation reactions to access cycloalkenes. Key mechanistic analysis based upon deuterium labelling will be presented suggesting that these reactions follow an unusual mechanistic pathway involving a 1,5-hydride shift. The final part of the talk will discuss how insight gained from these experiments has enabled the development of a second-generation approach capable of delivering cyclic scaffolds with very high levels of chemoselectivity, regioselectivity, and stereoselectivity.Natalia LarionovaElliot Davenport1,2Daniela Roman1Geoff Badman1David M. Lindsay2William J. Kerr21GSK2University of Strathclyde\n <!--EMPTY>Isotopically labelled compounds are essential for the drug development process [1]. Isotopologues enriched with stable isotopes, such as carbon-13 and deuterium, are invaluable in quantitative bioanalysis, where they can be used as internal standards for LCMS/MS based assays. Meanwhile, radiolabelled compounds provide unique access to crucial ADME data through in vivo studies, in both animals and humans [2].The field of isotopologue synthesis presents a unique set of challenges to synthetic chemists, who, with a limited and generally highly expensive pool of labelled reagents, must efficiently incorporate either stable or radioisotopes into drug structures. Due to the frequent presence of methyl groups in drug structures, a general late-stage methylation methodology, which allows for the incorporation of both carbon and hydrogen isotopes, has been identified as a powerful and desirable transformation. While conceptually simple, generally applicable methods which utilise accessible, isotopically enriched methylating agents, and which can be applied to late-stage intermediates, are limited [3].This talk outlines how a highly efficient and robust methodology for the methylation of aryl chlorides was identified using high throughput experimentation (HTE) [4]. In order to apply the chemistry to isotopologue synthesis, we have also developed a practically straightforward route to isotopically labelled potassium methyltrifluoroborate—a species which had not previously been obtained as a 13/14C-enriched isotopologue. It is envisaged that this methodology will be highly applicable to the synthesis of numerous isotopologues, which has been exemplified, notably, through use towards a number of drug-like scaffolds and within active GSK projects.References1. \n C. S. Elmore and R. A. Bragg, “ Isotope Chemistry; a Useful Tool in the Drug Discovery Arsenal,” Bioorganic & Medicinal Chemistry Letters 25, (2015): 167–171.2. \n J. Atzrodt, V. Derdau, W. J. Kerr, and M. Reid, “ Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences,” Angewandte Chemie, International Edition 57, (2018), 1758–1784.3. \n R. W. Pipal, K. T. Stout, P. Z. Musacchio, et al., “ Metallaphotoredox Aryl and Alkyl Radiomethylation for PET Ligand Discovery,” Nature 589, (2021): 542–547.4. \n E. Davenport, D. E. Negru, G. Badman, D. M. Lindsay, and W. J. Kerr, “ Robust and General Late-Stage Methylation of Aryl Chlorides: Application to Isotopic Labeling of Drug-Like Scaffolds,” ACS Catalysis 13, (2023): 11541–11547.David AudisioDepartment of Bio-organic Chemistry and Isotope Labelling, CEA-Saclay, Université Paris Saclay, Gif-sur-Yvette, FranceCarbon-14 radiolabelling is a unique tool that, in association with β-counting and β-imaging technologies, provides vital knowledge on the fate of synthetic organic molecules, such as pharmaceuticals and agrochemicals [1]. However, traditional multistep radio-synthesis and the associated costs have limited its utilization.Our group is interested in the development of novel methodologies, compatible with all carbon radioisotopes, which enables their insertion at a late-stage of the synthesis, while utilizing the simplest isotope sources such as carbon dioxide [14C]CO2, carbon monoxide [14C]CO and cyanides [14C]CN−.References1. \n R. Voges, J. R. Heys, and T. Moenius, Preparation of Compounds Labeled With Tritium and Carbon-14 (John Wiley & Sons, Ltd, 2009).2. \n(a) A. Del Vecchio, F. Caillé, A. Chevalier, et al., “ Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly From CO2,” Angewandte Chemie, International Edition, 57, (2018): 7944–9748. \n (b) G. Destro, O. Loreau, et al., “ Dynamic Carbon Isotope Exchange of Pharmaceuticals With Labeled CO2,” Journal of the American Chemical Society 141, (2019): 780–784. \n (c) G. Destro, K. Horkka, O. Loreau, et al., “ Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic Acids,” Angewandte Chemie, International Edition 59, (2020): 13490–13495. \n (d) V. Babin, A. Talbot, A. Labiche, et al., “ Photochemical Strategy for Carbon Isotope Exchange With CO2,” ACS Catalysis 11, (2021): 2968–2976. \n (e) M. Feng, J. De Oliveria, A. Sallustrau, et al., “ Direct Carbon Isotope Exchange of Pharmaceuticals via Reversible Decyanation,” Journal of the American Chemical Society 143, (2021): 5659–5665. \n (f) A. Ohleier, A. Sallustrau, B. Mouhsine, F. Caillé, D. Audisio, and T. Cantat, “ Catalytic Methoxylation of Aryl Halides using 13C- and 14C-Labeled CO2,” Chemical Communications 58, (2022): 12831–12834. \n (g) H. Cahuzac, A. Sallustrau, C. Malgorn, et al., “ Monitoring in Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging,” Journal of Medicinal Chemistry 65, (2022): 6953–6968. \n (h) S. Monticelli, A. Talbot, P. Gotico, et al., “ Unlocking Full and Fast Conversion in Photocatalytic Carbon Dioxide Reduction for Applications in Radio-Carbonylation,” Nature Communications 14, (2023): 4451. \n (i) A. Malandain, M. Molins, A. Hauwelle, et al., Journal of the American Chemical Society 145, (2023): 16760–16770.R. Bou Moreno1D. Hajdu1C. Winfield1D. Paumier1M. Preigh2R. Cosford2A. Oliver2J. Evarts21Eurofins Selcia2Day One BiopharmaceuticalsDAY101 or Tovorafenib is a Type 2 pan-RAF kinase inhibitor undergoing development as an alternative for the treatment of paediatric Low-Grade Glioma (pLGG). It is currently in Phase 2 for relapsed p-LGG and Phase 3 for frontline p-LGG. This presentation describes the synthesis by introduction of [14C]carbon dioxide onto the thiazole moiety, followed by further functionalisation and final chiral separation to obtain [thiazolecarbonyl-14C]DAY101 with good overall recovery and high enantiomeric purity. [thiazolecarbonyl-14C]DAY101 was then repurified under GMP to provide material suitable for hADME studies.\n <!--EMPTY>The non-GMP synthesis of the was performed by introduction of the labelled carbon as a pendant carboxylic acid into a commercially available thiazole using 14CO2. Functional group modification and incorporation of the pyridine and pyrimidine moieties furnished a racemic carbon-14 labelled precursor. Chiral separation of the enantiomers by HPLC followed by radio-dilution to a medium specific activity provided a technical batch of [thiazolecarbonyl-14C]DAY101 that was used for radio-stability testing and trial Drug Product manufacture. The technical batch was subsequently used as the starting material for a GMP purification.A stability study on the medium specific activity non-GMP batch of [thiazolecarbonyl-14C]DAY101 over 12 weeks at < −70°C showed steady degradation of radio-purity and UV purity by RP-HPLC. Alignment of the GMP manufacture with the study was necessary to ensure that the GMP [thiazolecarbonyl-14C]DAY101 was of suitable quality when dosed during the hADME study.Manufacture of a GMP batch of [thiazolecarbonyl-14C]DAY101 Drug Substance by repurification of the technical batch was subsequently performed in a time and material efficient manner within a dedicated GMP radiosynthesis laboratory and used to manufacture the Drug Product dosed in a human hADME study.L. S. Natrajan1,2M. B. Andrews1D. L. Jones1,3A. W. Woodward1M. A. Williams1,3A. N. Swinburne1J. R. Lloyd3S. Shaw3S. W. Botchway4A. D. Ward41Centre for Radiochemistry Research, Department of Chemistry The University of Manchester, UK2The Photon Science Institute, The University of Manchester, UK3Department of Earth, Atmospheric and Environmental Sciences, The University of Manchester, UK4The Science and Technology Facilities Council, Rutherford Appleton Laboratory, UKThe world currently holds a substantial nuclear legacy arising from fission activities, with a large proportion of high activity wastes that pose a radiological threat to natural and engineered environments. The decision to dispose of these high level wastes (following separation) in a suitable geological disposal facility (GDF) has provided some of the most demanding technical and environmental challenges facing the world in the coming century. In order to address these issues, we have begun a program of work to establish a comprehensive understanding of the electronic properties and physical and chemical properties of the radioactive actinide metals using state of the art emission spectroscopic techniques [1] in order to probe actinide speciation at submicron resolution over a given time period.I will discuss the potential to use the inherent fluorescent properties of the uranyl cation to study redox speciation in uranium-containing environmental samples by one and two-photon confocal fluorescence and phosphorescence microscopy and lifetime image mapping (Figure 1). Previous studies carried out on crystalline samples have shown that uranyl species are capable of experiencing two-photon excitation. Here, we study uranyl species in solution at room temperature and report fundamental properties such as quantum yield, two-photon excitation and emission spectra and two-photon cross sections. These capabilities are then applied to confocal fluorescence microscopy of uranyl in a range of bacterial and mineral samples, to study and map potentially useful process in (bio)remediation strategies including incorporation, biosorption and the in situ enzymatic reduction of uranyl [2, 3].References1. \n L. S. Natrajan, “ Developments in the Photophysics and Photochemistry of Actinide Ions and Their Coordination Compounds,” Coordination Chemistry Reviews 256, (2012): 1583–1603.2. \n D. L. Jones, M. B. Andrews, A. N. Swinburne, et al., “ Fluorescence Spectroscopy and Microscopy as Tools for Monitoring Redox Transformations of Uranium in Biological Systems,” Chemical Science 6, (2015): 5133–5138.3. \n M. B. Andrews, D. L. Jones, A. W. Woodward, et al., “ Multiphoton Imaging of Spatial Distribution, Coordination and Redox Environment of Uranium under Model Biogeochemical Conditions,” ChemRxiv, 2023, https://doi.org/10.26434/chemrxiv-2023-lvvtz.","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 10","pages":"349-356"},"PeriodicalIF":0.9000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jlcr.4115","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of labelled compounds & radiopharmaceuticals","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jlcr.4115","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}

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Abstract

Matthew J. Fuchter¹

Department of Chemistry Imperial College London

Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications, from molecular motors, memory, and manipulators to solar thermal storage. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one or both of the aryl rings from the conventional azobenzene class has been replaced with a heteroaromatic ring. This talk will give an overview of our work in this area, initially focusing on our discovery of the arylazopyrazoles [1], which offer quantitative photoswitching and high thermal stability of the Z isomer. It will go on to describe our elucidation of structure–property relationships for a wide array of comparable azoheteroaryl photoswitches [2, 3]. Through this, we have identified compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics, all through tuning of the heteraromatic ring.

Given the large tunability of their properties, the predictive nature of their performance, and the other potential functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potential in a wide range of optically addressable applications. This talk will particularly focus on the promise of such agents in photopharmacology: light-addressable drugs [4–6].

References

1. C. E. Weston, R. D. Richardson, P. R. Haycock, A. J. P. White, and M. J. Fuchter, “ Arylazopyrazoles: Azoheteroarene Photoswitches Offering Quantitative Isomerization and Long Thermal Half-Lives,”Journal of the American Chemical Society 136, (2014): 11878–11881.

2. J. Calbo, C. E. Weston, A. J. P. White, H. Rzepa, J. Contreras-García, and M. J. Fuchter, “ Tuning Azoheteroarene Photoswitch Performance Through Heteroaryl Design,” Journal of the American Chemical Society 139, (2017): 1261–1274.

3. A. Gonzalez, M. Odaybat, M. Le, et al., “ Photocontrolled Energy Storage in Azobispyrazoles With Exceptionally Large Light Penetration Depths,” Journal of the American Chemical Society 144, (2022): 19430–19436.

4. C. E. Weston, A. Kraemer, F. Colin, et al., “ Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors,” ACS Infectious Diseases 3, (2017): 152–161.

5. P. Y. Lam, A. R. Thawani, E. Balderas, et al., “ TRPswitch—A Step-Function Chemo-Optogenetic Ligand for the Vertebrate TRPA1 Channel,” Journal of the American Chemical Society 142, (2020): 17457–17468.

6. M. J. Fuchter, “ On the Promise of Photopharmacology Using Photoswitches: A Medicinal Chemist’s Perspective,” Journal of Medicinal Chemistry 63, (2020): 11436–11447.

Alex Cresswell

Department of Chemistry, University of Bath

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