A5025887280- Adenosine and Purinergic Signaling
- Synthetic Organic Chemistry Methods
- Receptor Mechanisms and Signaling
- Asymmetric Synthesis and Catalysis
- Pharmacological Receptor Mechanisms and Effects
- Coordination Chemistry and Organometallics
- Chemokine receptors and signaling
- Chemical Synthesis and Analysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- interferon and immune responses
- Analytical Chemistry and Chromatography
- Immunotherapy and Immune Responses
- Synthesis of heterocyclic compounds
- Monoclonal and Polyclonal Antibodies Research
- GABA and Rice Research
- Neuroscience and Neuropharmacology Research
- Synthesis and Biological Evaluation
- Fluorine in Organic Chemistry
- Mesoporous Materials and Catalysis
- Electroconvulsive Therapy Studies
- Cannabis and Cannabinoid Research
- Neuropeptides and Animal Physiology
- Multicomponent Synthesis of Heterocycles
- Sphingolipid Metabolism and Signaling
University of Nottingham
2016-2024
University of Birmingham
2019-2024
Loughborough University
1996-2017
AstraZeneca (United Kingdom)
2001-2017
University of Oxford
2004-2009
University of Cambridge
1988-1996
Research & Development Institute
1995
University of Wisconsin–Madison
1990
The platelet P2T receptor plays a major role in aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We explored analogues of adenosine triphosphate (ATP), which is weak, nonselective but competitive antagonist. Modification the polyphosphate side chain prevent breakdown agonist diphosphate (ADP) substitution adenine moiety enhance affinity selectivity for led identification 10e (AR-C67085MX), having an IC50 2.5 nM against...
CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages has antimicrobial properties. also implicated in the pathology inflammatory disorders progression several cancers, its expression increased during viral infections lung. However, exact role health disease requires further investigation, there need for confirmed molecular targets mediating functional responses. Using range bioluminescence resonance...
Abstract To study the localisation of G protein-coupled receptors (GPCR) in their native cellular environment requires visualisation through fluorescent labelling. overcome requirement for genetic modification receptor or limitations dissociable ligands, here we describe rational design a compound that covalently and selectively labels GPCR living cells with moiety. We designed antagonist, which linker incorporated between pharmacophore (ZM241385) fluorophore (sulfo-cyanine5) is able to...
The study of protein function and dynamics in their native cellular environment is essential for progressing fundamental science. To overcome the requirement genetic modification or limitations dissociable fluorescent ligands, ligand-directed (LD) chemistry has most recently emerged as a complementary, bioorthogonal approach labeling proteins. Here, we describe rational design, development, application first A1AR living cells. We pharmacologically demonstrate covalent expressed cells while...
Among class A G protein-coupled receptors (GPCR), the human adenosine A2A receptor (hA2AAR) remains an attractive drug target. However, translation of A2AAR ligands into clinic has proved challenging and improved understanding pharmacology could promote development more efficacious therapies. Subtype-selective fluorescent probes would allow detailed real-time pharmacological investigations both in vitro vivo. In present study, two families were designed around known hA2AAR selective...
The C–X–C chemokine receptor type 4, or CXCR4, is a found to promote cancer progression and metastasis of various cell types. To investigate the pharmacology this receptor, further elucidate its role in cancer, novel chemical tools are necessity. In present study, using classic medicinal chemistry approaches, small-molecule-based fluorescent probes were designed synthesized based on previously reported small-molecule antagonists. Here, we report development three distinct classes that show...
Reaction of hindered lithium amides with readily available (enantiopure) terminal epoxides gives 2-ene-1,4-diols via carbenoid dimerization the corresponding α-lithiated epoxides. d-Mannitol and d-iditol were synthesized using this method in three steps from (S)-tritylglycidyl ether.
A new reactivity mode of lithium amides with epoxides leads to hindered enamines. The reaction some these enamines unactivated primary and secondary alkyl halides is described, which expands the range electrophiles that one can use in synthesis mono-alkylated aldehydes.
In vitro synthesis of the iron-molybdenum cofactor (FeMo-co) dinitrogenase using homocitrate and its analogs allows formation modified forms FeMo-co that show altered substrate specificities (N2, acetylene, cyanide, or proton reduction) nitrogenase [reduced ferredoxin:dinitrogen oxidoreductase (ATP-hydrolyzing), EC 1.18.6.1]. The (1R,2S)-threo- (1S,2S)-erythro-fluorinated diastereomers have been incorporated in into place homocitrate. Dinitrogenase activated with synthesized...
1. The role of endogenous ADP in platelet aggregation vivo remains unclear due to the lack suitable P2T-antagonist probes. This paper describes potency, selectivity and specificity novel P 2T-purinoceptor antagonist, FPL 67085 (2-propylthio-D-beta,gamma-dichloromethylene ATP) both vitro anaesthetized rat vivo. 2. (3-30 nM) produced concentration-dependent rightward displacement concentration-effect (E/[A]) curve for ADP-induced human washed platelets with no effect on ADP-independent at < or...
The conjugate addition of the phenyldimethylsilyl-cuprate reagent to cinnamate and crotonate esters amides various known chiral auxilaries is diastereoselective, making available β-silylesters high enantiomeric excess; sense diastereoselectivity anomalously different from established precedent in case silyl-cuprate ester (1, R = Ph, R*=d).
A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde enamines are produced via a previously unrecognized reaction pathway. Some these display unprecedented C-alkylation toward unactivated primary and secondary alkyl halides. For comparison, the synthesized traditional condensation method was examined. C- rather than N-alkylation dominant pathway found range electrophiles, making this route to α-alkylated aldehydes more synthetically useful reported.
N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in CCR4 receptor antagonist high-throughput screen (HTS) of subset the AstraZeneca compound bank. As with lead-like profile, it an excellent starting point for program and enabled rapid progression through Lead Identification Optimization phases resulting discovery two bioavailable candidate drugs.
The human P2Y2 receptor (hP2Y2R) is a G-protein-coupled that shows promise as therapeutic target for many important conditions, including antimetastatic cancer and more recently idiopathic pulmonary fibrosis. As such, there need new hP2Y2R antagonists molecular probes to study this receptor. Herein, we report the development of series non-nucleotide antagonists, based on known, antagonist AR-C118925 (1), leading discovery fluorescent ligands containing different linkers fluorophores. One...
The adenosine A1 receptor (A1AR) is a G-protein-coupled (GPCR) that provides important therapeutic opportunities for number of conditions including congestive heart failure, tachycardia, and neuropathic pain. development A1AR-selective fluorescent ligands will enhance our understanding the subcellular mechanisms underlying A1AR pharmacology facilitating more efficacious selective therapies. Herein, we report design, synthesis, application novel series probes based on 8-functionalized...
The conjugate addition of the phenyldimethylsilyl-cuprate reagent to cinnamate and crotonate esters amides 1 various known chiral auxiliaries, a–e, is diastereoselective. sense diastereoselectivity silyl-cuprate 1b–d, 8 9 different from established precedent based on carbon-cuprates, but normal for amide 1a, imides 1e 21, oxazolidine 6. auxiliary e gives best results those tested, silicon-containing group can be removed using alkoxide ion in aprotic media, making available β-silyl 27–29 high...
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use the tricyclic to synthesize potent inhibitors serine peptidase DPP-4, antagonists CCR5 receptor, highly selective PI3K δ isoform inhibitors. We also describe predicted physicochemical properties resulting conclude that tractable could potential application in future drug discovery programs.
The homochiral pentadienylsilanes (3Z,5E)-(hepta-3,5-dien-2-yl)dimethyl(phenyl)silane 9, (3Z,5E)-(hepta-3,5-dien-2-yl)trimethylsilane 13, (4Z,6E)-(2-methylocta-4,6-dien-3-yl)dimethyl(phenyl)silane 14 and (4Z,6E)-(2-methylocata-4,6-dien-3-yl)trimethylsilane 17 undergo Lewis acid catalysed reactions with isobutyraldehyde its dimethyl acetal stereospecifically anti surprisingly high levels of stereoselectivity, ca. 90:10. (3Z)-hexa-3,5-dien-2-yldimethyl(phenyl)silane 20aa,...