Article
Chemistry, Organic
Kentaro Iwaki, Kazuhiro Tanagawa, Soichiro Mori, Koki Maruno, Yuji Sumii, Osamu Nagata, Norio Shibata
Summary: In this study, we reported a metal-free hydration reaction of pyridine-SF4-alkynes under acidic conditions, which synthesized pyridine-SF4-methyl ketones with yields ranging from 59% to 93%. We further demonstrated the synthetic applications of these compounds, including chlorination, NaBH4 reduction, Baeyer-Villiger oxidation, and the generation of enol triflates. These compounds show promise as useful building blocks in the synthesis of a wide range of SF4-containing drug candidates.
Article
Chemistry, Organic
Xi Chen, Zhe Zhang, Wei-Yu Shi, Ya-Nan Ding, Yu-Yong Luan, Yan-Chong Huang, Qiang Wang, Xue-Yuan Liu, Yong-Min Liang
Summary: We report a redox-neutral, visible-light-mediated difluoroalkylation of unactivated C(sp(3))-H bonds in amides via nitrogen-centered radicals triggered intramolecular hydrogen atom transfer. All types of gamma-C(sp(3))-H bonds exhibited excellent reactivity. This methodology provides a facile route for regioselective introduction of alpha,alpha-difluoroketonefragments into organic molecules, which can be easily converted to structurally diverse difluoro-containing molecules with broad potential applications in medicinal chemistry and chemical biology.
Article
Chemistry, Physical
Ming-Sheng Xie, Meng Shan, Ning Li, Yang-Guang Chen, Xiao-Bing Wang, Xuan Cheng, Yin Tian, Xiao-Xia Wu, Yun Deng, Gui-Rong Qu, Hai-Ming Guo
Summary: An efficient chiral 4-aryl-pyridine-N-oxide (ArPNO) nucleophilic organocatalyst was designed, synthesized, and successfully applied in the dynamic kinetic resolution of azoles, aldehydes, and anhydrides, providing high yields, excellent enantioselectivity, and structural diversity. Mechanistic studies revealed the key role of acyloxypyridinium cation formation and the higher nucleophilic ability of oxygen in pyridine-N-oxide, contributing to the development of diverse chiral 4-substituted pyridine-N-oxides as efficient nucleophilic organocatalysts.
Article
Chemistry, Organic
Lei Bao, Zhi-Xiang Wang, Xiang-Yu Chen
Summary: In this study, we reported a method for the photoreduction of acyl fluorides using N-heterocyclic nitrenium iodide salt as catalyst to generate acyl radicals, which can react with 2-isocyanobiaryls to form various carbonyl phenanthridines.
Article
Chemistry, Organic
Li-Chen Xu, Xiao-Di Ma, Kun-Ming Liu, Xin-Fang Duan
Summary: In this study, a new method is proposed to achieve regioselective alkylation of pyridines at the C2 position, providing an important synthetic tool for late-stage diversification of drugs.
Article
Chemistry, Organic
Jiadi Zhou, Cheng Cheng, Zhihao Lin, Quanlei Ren, Ning Xu, Jiangfeng Lin, Yimin Qin, Jianjun Li
Summary: An efficient silver-catalyzed d-regioselective C(sp(3))-H heteroarylation of free alcohols has been developed, allowing for selective activation of different types of d-C(sp(3))-H bonds in alcohols and providing a new platform for diverse functionalizations of alcohols and heteroaryls.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Article
Chemistry, Physical
Aleena Pious, Ravi Kanth Kamlekar, Sureshan Muthusamy, Arunachalam Jothi, Vijayendran K. K. Praneeth, Subburethinam Ramesh, Anbazhagan Veerappan
Summary: This study successfully synthesized a series of amphiphilic molecules, PyNAGs, with varying hydrophobicity, and characterized their self-assembly properties. The PyNAGs with a N-stearoyl moiety exhibited lower critical micellar concentration (CMC), higher aggregation number (Nagg), and larger diameter (DH) compared to PyNAGs with a N-lauryl moiety. Molecular dynamics simulation revealed a compact micelle structure with non-bonded energy contribution from electrostatic and van der Walls forces. The ability of PyNAG micelles to perform organic transformations in water was demonstrated through the Povarov reaction, showing higher yield in N-stearoyl-N-(pyridin-2-ylmethyl)glycine (PyN18G) micelles compared to organic solvent and commercial surfactants. A linear correlation between yield and PyNAG hydrophobicity was observed, highlighting the significant impact of micellar interior on substrate reactivity in metal-catalyzed green synthesis.
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
(2023)
Article
Chemistry, Multidisciplinary
Animesh Biswas, Jorg-M Neudoerfl, Nils E. Schlorer, Albrecht Berkessel
Summary: Azolium enolates and acyl azolium cations serve as crucial intermediates in N-heterocyclic carbene (NHC) catalyzed reactions, with acetyl azolium enolates showing selective reactivity towards alcohol nucleophiles. The formation of esters is proposed to originate from azolium enolate intermediates rather than acyl azolium cations.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Inorganic & Nuclear
Xiaoxiao Cui, Xiujia Hao, Fang Guo
Summary: This paper describes the synthesis of three N-heterocyclic carbene complexes by stepwise grinding and their application as catalysts in C-S bond cross-coupling reactions.
DALTON TRANSACTIONS
(2022)
Article
Chemistry, Organic
Chuncheng Zou, Yanting Lv, Min Lu, Xin Li, Lei Zhang, Lei Yang, Zhen Liu, Yanxiong Ke, Gonghua Song, Jinxing Ye
Summary: This study reported regioselective and diastereodivergent asymmetric vinylogous Michael addition between beta-substituted-cyclohexenones and nitroalkenes using complementary chiral aminocatalysts. The reactions showed high enantio- and diastereoselectivities, with DFT calculations explaining the stereochemistry control through hydrogen-bonding interaction and steric hindrance effects. Additionally, the diverse configurations of the adducts led to enantioenriched spirocyclic ketones and cis-2-decalones with multiple chiral centers.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Article
Chemistry, Organic
Sung June Kim, Sunhee Lee, Ikyon Kim
Summary: In this study, the expansion of nitrogen-fused heteroaromatic chemical space, such as indolizine and pyrrolo[1,2-a]pyrazine, was achieved through FeCl3-catalyzed nucleophilic addition of these compounds to a wide range of azolinium systems, resulting in novel N-fused heteroaromatic scaffolds with regioselective dearomatized N-heterocyclic substituents. Nucleophilic addition of indolizines and pyrrolo[1,2-a]pyrazines mainly occurred at the C1 position of isoquinoliniums and at the C4 site of quinoliniums.
SYNTHESIS-STUTTGART
(2021)
Article
Chemistry, Organic
Shen Ge, Yi-Ming Zhu, Xiao-Ping Xu, Shun-Jun Ji
Summary: A palladium-catalyzed three-component reaction was used for the one-pot synthesis of 2-(trifluoromethyl)-quinazolin-4(3H)-imines, using isocyanides, 2,2,2-trifluoro-N-(2-iodophenyl)acetimidoyl chlorides, and amines. The protocol offers a wide substrate scope, high efficiency, and readily available raw materials.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Zelun Zhao, Guang Gao, Yongjie Xi, Jia Wang, Peng Sun, Qi Liu, Wenjun Yan, Yi Cui, Zheng Jiang, Fuwei Li
Summary: In this study, a sustainable approach to produce valuable hydroxyalkanoates from cellulose-derived furans via coupling homogeneous carbonylation and heterogeneous hydrogenation was demonstrated. The use of 8Ni/CeO2 catalyst in the hydrogenation reaction showed high selectivity and stability.
Article
Chemistry, Multidisciplinary
Yi Liu, Cuihan Zhou, Meijing Jiang, Bruce A. Arndtsen
Summary: We have developed a general palladium-catalyzed method to synthesize acyl fluorides from different types of compounds. Mechanistic analysis suggests that the reaction proceeds through the combination of visible light photoexcitation of Pd(0) with a ligand-favored reductive elimination, resulting in a unidirectional catalytic cycle. Coupling this catalytic method with nucleophilic reactions allows for a broad range of carbonylation reactions, including the synthesis of highly functionalized products.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Jindian Duan, Yiyang Mao, Anmei Xian, Binsen Rong, Gaochen Xu, Zhenjiang Li, Lili Zhao, Ning Zhu, Kai Guo
Summary: A copper-catalyzed regioselective [3+2] annulation of malonate-tethered acyl oximes with isatins was developed, providing valuable 2,3-dihydrooxazole-spirooxindoles in moderate to good yields with excellent diastereoselectivity. The reaction involves Cu(I) initiated multiple steps, featuring mild reaction conditions and broad substrate scope. DFT calculations demonstrated that the [3+2] annulation pathway is energetically favorable both in kinetics and thermodynamics.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Organic
Stuart C. Davidson, Gabriel dos Passos Gomes, Leah R. Kuhn, Igor Alabugin, Alan R. Kennedy, Nicholas C. O. Tomkinson
Summary: The treatment of sulfide with a 1,3-diketone in the presence of silica sulfuric acid and hydrogen peroxide leads to the corresponding sulfoxide product. The tris-peroxide formed in the reaction can oxidize sulfide and experimental observations suggest a mechanism involving acid-catalyzed ring opening.
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.