Article
Chemistry, Multidisciplinary
Nagaraju Sakkani, Dhiraj K. Jha, Emily Whatley, John C-G Zhao
Summary: In this study, the direct synthesis of alpha-acyloxylketones from ketones and readily available carboxylic acids was achieved using a photo-assisted halogen bond-mediated organocatalytic reaction. This method holds significance in the synthesis of pharmaceuticals and biologically active products.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Matteo Balletti, Enrico Marcantonio, Paolo Melchiorre
Summary: Reported in this study is a rare example of asymmetric catalytic functionalization of enals at the remote gamma-position through a radical pathway. This process utilizes the synergistic actions of two distinct organocatalysts and requires visible light irradiation.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Zhibing Weng, Ying Zhou, Xin Yue, Feng Jiang, Wengang Guo
Summary: In this study, catalytic asymmetric alpha-regioselective Michael additions of vinylogous alpha-ketoester enolates were conducted efficiently using a chiral bifunctional organocatalyst. The reactions yielded Rauhut-Currier type products with high yields and excellent regio- and enantioselectivities.
Article
Chemistry, Multidisciplinary
Lisa-Marie Mohr, Christina H. McCulley, Jakob Blom, Johannes N. Lamhauge, Karl Anker Jorgensen
Summary: The study investigated the organocatalytic enantioselective alpha-chlorination of 2-phenylpropanal and found that primary aminocatalysts can catalyze the formation of alpha-chloro branched aldehydes with moderate enantioselectivities. Experimental and computational investigations were conducted to understand the challenges in achieving high enantioselectivity for this reaction. Lack of control over the formation of (E)- and (Z)-enamine intermediates and clustering of reaction barriers were identified as key factors contributing to the difficulties in producing high enantioselectivity.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Organic
Alejandro Torregrosa-Chinillach, Asier Carral-Menoyo, Enrique Gomez-Bengoa, Rafael Chinchilla
Summary: A highly efficient enantioselective alpha-nitrogenation method has been developed for synthesizing alpha,alpha-disubstituted alpha-nitrogenated aldehydes without the need for any solvents, achieving high yields and excellent enantioselectivities. The sustainability and rationality of the method have been demonstrated through green metrics calculation and theoretical calculations.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Wei Wang, Zhaoliang Qin, Ze Tan, Wen Yang
Summary: An efficient organocatalytic enantioselective cross-aldol reaction of aryl ketones with heteroaromatic trifluoromethyl ketone hydrates via enolate intermediates has been developed. The cross-aldol reactions catalyzed by Takemoto-type thiourea catalysts proceeded well under mild conditions, furnishing a variety of enantioenriched alpha-trifluoromethyl tertiary alcohols bearing N-heteroaromatics with good to high yields and enantioselectivities. This protocol features broad substrate scope, good functional group tolerance, and easy gram-scale preparation.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Rachid Chahboun, Jose Manuel Botubol-Ares, Maria Jesus Duran-Pena, Fermin Jimenez, Ramon Alvarez-Manzaneda, Enrique Alvarez-Manzaneda
Summary: This study presents a general and efficient method for the deconjugative alpha-alkylation of alpha,beta-unsaturated aldehydes under mild conditions through a synergistic effect between (BuOK)-Bu-t and NaH. The resulting beta,gamma-unsaturated aldehyde can be transformed into the corresponding allyl acetate via lead(IV) acetate-mediated oxidative fragmentation, with high yield. This strategy is applicable for constructing the carbon skeleton of diverse alkyl or aryl terpenoids.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Joydev K. Laha, Upma Gulati, Anjali Gupta
Summary: A decarboxylative amidation of aryl/heteroarylacetic acids by reaction with NHS and tert-butyl nitrite has been reported, which offers a convenient method for the synthesis of aliphatic and (hetero)aromatic amides. Mechanistic studies reveal a previously unexplored pathway involving traceless alpha-functionalized benzylic radicals for the formation of activated ester, followed by one-pot reaction with amines to form amides. The gram-scale synthesis of Moclobemide demonstrates the practical applicability of this method.
Article
Chemistry, Multidisciplinary
Pawel Huninik, Jakub Szyling, Agnieszka Czapik, Jedrzej Walkowiak
Summary: An efficient and simple method for the regioselective hydroboration of alkenes has been developed using pinacolborane and 1-ethyl-methylpyrrolidinium triflate as the reducing reagent and organocatalyst respectively. The protocol is scalable and compatible with various alkenes, providing moderate-to-excellent yields of organoboron compounds. The obtained alkylboronates can be further used in various transformations, and a reaction mechanism has been proposed based on literature and NMR studies.
Article
Chemistry, Organic
George Hutchinson, Carla Alamillo-Ferrer, Martin Fernandez-Pascual, Jordi Bures
Summary: The Nanjing Huamu Football Team has developed a number of outstanding players over the past 7 years and has made significant contributions to the local youth football movement.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Masanori Yoshida
Summary: The enantioselective alpha-allylation and -propargylation of alpha-branched aldehydes with alkyl halides were successfully achieved using a chiral primary amino acid organocatalyst. The reaction proceeded smoothly in a mildly basic aqueous solution of potassium hydrogen carbonate, providing alpha-allylated or -propargylated aldehydes in good yield (up to 87%) and high enantioselectivity (up to 96% ee).
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Min-Song Wu, Zhi-Yong Han, Liu-Zhu Gong
Summary: A regioselective asymmetric a-pentadienylation reaction of aldehydes was developed by utilizing readily available cyclopropylacetylene and its derivatives as the pentadienylation reagent, with the cooperative catalysis of a chiral Pd(0) catalyst and a chiral Bronsted acid, in the presence of a substoichiometric amount of an achiral amine. The reaction resulted in high yields and enantioselectivities, as well as excellent E/Z ratios of the alpha-pentadienylation products.
Review
Chemistry, Physical
Bakhtar Ullah, Navneet Kumar Gupta, Quanli Ke, Naseeb Ullah, Xingke Cai, Dongqing Liu
Summary: Alpha-aminonitriles are important compounds in pharmacology with various properties, and they can be used to synthesize amino acids. The commercialization of these compounds is challenging due to the need for large-scale production with controlled chirality. Recent developments in organocatalysis have provided a promising alternative method for synthesizing alpha-aminonitriles, which may contribute to the development of new industrial catalysts.
Article
Chemistry, Multidisciplinary
Wengang Guo, Min Wang, Zhengyu Han, Hai Huang, Jianwei Sun
Summary: The research describes the first organocatalytic asymmetric N-H insertion reaction using alpha-carbonyl sulfoxonium ylides, providing efficient access to alpha-aryl glycines with excellent enantiocontrol. The high stability and weak basicity of sulfoxonium ylides make this protocol user-friendly and practically useful, with detailed mechanistic studies revealing reversible protonation and rate-determining C-N bond formation.
Article
Chemistry, Organic
Yoseop Kim, Seung Yeon Kim, Sung-Gon Kim
Summary: A new asymmetric annulation reaction was developed to efficiently synthesize enantioenriched polyheterotricyclic imidazolidines and oxazolidines.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Michael A. Clegg, Natalie H. Theodoulou, Paul Bamborough, Chun-wa Chung, Peter D. Craggs, Emmanuel H. Demont, Laurie J. Gordon, Gemma M. Liwicki, Alex Phillipou, Nicholas C. O. Tomkinson, Rab K. Prinjha, Philip G. Humphreys
Summary: Selective small molecule bromodomain inhibitors developed by researchers have potential for future development of small molecules to study TAF1(2) biology, with key impact from modulating the basicity of a pendant amine.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Philip G. Humphreys, Stephen J. Atkinson, Paul Bamborough, Rino A. Bit, Chun-Wa Chung, Peter D. Craggs, Leanne Cutler, Rob Davis, Alan Ferrie, GangLi Gong, Laurie J. Gordon, Matthew Gray, Lee A. Harrison, Thomas G. Hayhow, Andrea Haynes, Nick Henley, David J. Hirst, Ian D. Holyer, Matthew J. Lindon, Cerys Lovatt, David Lugo, Scott McCleary, Judit Molnar, Qendresa Osmani, Chris Patten, Alex Preston, Inmaculada Rioja, Jonathan T. Seal, Nicholas Smithers, Fenglai Sun, Dalin Tang, Simon Taylor, Natalie H. Theodoulou, Clare Thomas, Robert J. Watson, Christopher R. Wellaway, Linrong Zhu, Nicholas C. O. Tomkinson, Rab K. Prinjha
Summary: Through regulation of the epigenome, the BET family of proteins are important therapeutic targets. This study describes the medicinal chemistry strategy to develop an orally bioavailable pan-BET candidate.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Christine Salaun, Hiroya Takizawa, Alex Galindo, Kevin R. Munro, Jayde McLellan, Isamu Sugimoto, Tomotaka Okino, Nicholas C. O. Tomkinson, Luke H. Chamberlain
Summary: Protein S-acylation is a reversible post-translational modification that regulates the localization and function of cellular proteins. This study developed a high-throughput assay to screen for compounds that interfere with the autoacylation of zDHHC2, an enzyme involved in neuronal S-acylation pathways. Two compounds were identified that inhibited both zDHHC2 autoacylation and substrate S-acylation, providing potential tools for studying the cellular activities of zDHHC enzymes in S-acylation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Liam Butler, Carolina Locatelli, Despoina Allagioti, Irina Lousa, Kimon Lemonidis, Nicholas C. O. Tomkinson, Christine Salaun, Luke H. Chamberlain
Summary: S-acylation is an important post-translational modification mediated by the zDHHC enzyme family. This study focused on the S-acylation of Sprouty and SPRED proteins by zDHHC17. Surprisingly, the zDHHC ANK binding motif (zDABM) was found to be dispensable for S-acylation in Sprouty-2, and SPRED3, which lacks zDABM, was efficiently S-acylated. Mutational analysis revealed that the cysteine-rich SPR domain of SPRED3 interacts with zDHHC17, independent of ANK17. Thus, zDHHC17 can recognize its substrates through both zDABM-dependent and zDABM-independent mechanisms.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Arron Aatkar, Aini Vuorinen, Oliver E. Longfield, Katharine Gilbert, Rachel Peltier-Heap, Craig D. Wagner, Francesca Zappacosta, Katrin Rittinger, Chun-wa Chung, David House, Nicholas C. O. Tomkinson, Jacob T. Bush
Summary: Sulfur(VI) fluorides (SFs) have been used as valuable electrophiles for designing covalent inhibitors that go beyond cysteine and have the potential to broaden the range of liganded proteome. By targeting nucleophilic amino acids, SFs provide a method for covalent protein modification without the need for a nearby cysteine residue. Libraries of reactive fragments containing SFs offer an innovative approach for ligand and tool discovery through mass spectrometry analysis. This study presents a screening approach that utilizes the unique properties of SFs, successfully identifying hit compounds for CAII and BCL6 through a direct-to-biology workflow. Further characterization of the most promising hits includes determining covalent modification sites, kinetics, and target engagement in cells, as well as a detailed molecular understanding through crystallography. This screening protocol holds potential for accelerated discovery of covalent inhibitors beyond cysteine.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Analytical
Henry J. Braddick, William J. Tipping, Liam T. Wilson, Harry S. Jaconelli, Emma K. Grant, Karen Faulds, Duncan Graham, Nicholas C. O. Tomkinson
Summary: This article reports the first ratiometric sensor for carboxylesterase (CE) activity using Raman spectroscopy based on a bisarylbutadiyne scaffold. The sensor showed high sensitivity and specificity for CE detection with low cellular cytotoxicity. It was successfully used for ratiometric detection of esterase activity in hepatocyte cells and detection of localized ultraviolet damage in a mixed cell population using stimulated Raman scattering microscopy coupled with spectral phasor analysis.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Sergej Maciuk, Susanna H. H. Wood, Vipulkumar K. K. Patel, Peter D. P. Shapland, Nicholas C. O. Tomkinson
Summary: The peracid oxidation of hydrocarbons in chlorinated solvents is a low yielding and poorly selective process, but can be improved through the addition of hydrogen bond donors and acceptors. Using strong HBD and poor HBA solvents, higher yields and selectivities of alcohol products can be achieved. This transformation shows selectivity for tertiary centers and is influenced by stereoelectronic effects, while primary centers are not oxidized.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
David J. Fallon, Alex Phillipou, Christopher J. Schofield, David House, Nicholas C. O. Tomkinson, Jacob T. Bush
Summary: This article presents the development and optimization of a photoaffinity labelling (PAL) displacement assay. It uses a highly efficient PAL probe to assess the relative binding affinities of compounds to specific binding sites in multiple recombinant protein domains in tandem. The assay was validated using a test set of 264 compounds annotated with activity against the bromodomain and extra-terminal domain (BET) family in ChEMBL. The obtained pIC50 values correlated well with orthogonal TR-FRET data, highlighting the potential of this accessible PAL biochemical screening platform.
BIOCHEMICAL JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Aristea Anna Leventi, Henry J. Braddick, Kharmen Billimoria, Gregory Q. Wallace, Heidi Goenaga-Infante, Nicholas C. O. Tomkinson, Karen Faulds, Duncan Graham
Summary: This article reports the synthesis of nanocarriers for delivering the antitumor drug cisplatin. Multimodal imaging techniques, including surface enhanced Raman scattering and laser ablation inductively coupled plasma time of flight mass spectrometry, were used to visualize the intracellular uptake of both the nanocarrier and drug.
CHEMICAL COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Ross P. P. Thomas, Emma K. K. Grant, Eleanor R. R. Dickinson, Francesca Zappacosta, Lee J. J. Edwards, Michael M. M. Hann, David House, Nicholas C. O. Tomkinson, Jacob T. T. Bush
Summary: The screening of covalent or 'reactive' fragment libraries against proteins has been limited in targeting cysteine residues. This study presents the development of a carboxylate-targeting reactive fragment screening platform using 2-aryl-5-carboxytetrazole (ACT) as the photoreactive functionality. The utility of ACT photoreactive fragments (ACT-PhABits) was evaluated by screening a small panel of purified proteins, and the selectivity of the ACT group was revealed through LC-MS/MS studies. A photosensitised approach to ACT activation was also developed, eliminating the need for high energy UV-B light.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Joseph Mason, Harry Wilders, David J. Fallon, Ross P. Thomas, Jacob T. Bush, Nicholas C. O. Tomkinson, Francesco Rianjongdee
Summary: Researchers have developed an automated, accurate, and easy-to-use program called PyParse for data extraction from high-throughput chemistry, which significantly improves the speed and accuracy of analysis. The open-source nature of this software package facilitates the widespread adoption of high-throughput chemistry and enables the creation of standardized chemistry datasets.
Article
Biochemistry & Molecular Biology
Brett Cosgrove, Emma K. Grant, Sophie Bertrand, Kenneth D. Down, Don O. Somers, John P. Evans, Nicholas C. O. Tomkinson, Michael D. Barker
Summary: The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIII beta is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.
RSC CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
William J. Tipping, Andrew S. Merchant, Rebecca Fearon, Nicholas C. O. Tomkinson, Karen Faulds, Duncan Graham
Summary: Stimulated Raman scattering (SRS) microscopy is a powerful technique for visualizing the uptake and distribution of drugs and small molecules in live cells. It can directly detect bioactive molecules and has potential for preclinical drug development. Real-time detection of drug-cell interactions allows for the assessment of drug uptake and distribution, providing important insights for drug development.
RSC CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Beatriz Romartinez-Alonso, Maura Agostini, Heulyn Jones, Jayde McLellan, D. Eilidh Sood, Nicholas Tomkinson, Federica Marelli, Ilaria Gentile, W. Edward Visser, Erik Schoenmakers, Louise Fairall, Martin Privalsky, Carla Moran, Luca Persani, Krishna Chatterjee, John W. R. Schwabe
Summary: This study reveals that TR alpha mutants associated with RTH alpha can still bind thyroid hormone, leading to the synthesis of a novel thyroid hormone analogue, ES08, which effectively dissociates mutant TR alpha from corepressor. ES08 shows promising results in rescuing developmental anomalies in a zebrafish model and inducing target gene expression in cells from RTH alpha patients.
MOLECULAR AND CELLULAR BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
William J. Tipping, Liam T. Wilson, Connie An, Aristea A. Leventi, Alastair W. Wark, Corinna Wetherill, Nicholas C. O. Tomkinson, Karen Faulds, Duncan Graham
Summary: Statins have shown potential anti-tumour activity in breast cancer treatment, but understanding their mode of action and accurately assessing their efficacy is challenging. This study demonstrates the use of stimulated Raman scattering (SRS) microscopy for characterising breast cancer cells treated with statins, revealing different lipid accumulation phenotypes associated with cell viability.
