A5065961187- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Asymmetric Hydrogenation and Catalysis
- Synthesis and Catalytic Reactions
- Asymmetric Synthesis and Catalysis
- Fluorine in Organic Chemistry
- Chemical Reaction Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Synthetic Organic Chemistry Methods
- Pharmacogenetics and Drug Metabolism
- Carbohydrate Chemistry and Synthesis
- Organoboron and organosilicon chemistry
- Molecular spectroscopy and chirality
- Organic Chemistry Cycloaddition Reactions
- Drug Transport and Resistance Mechanisms
- Receptor Mechanisms and Signaling
- Catalytic Cross-Coupling Reactions
- Crystallography and molecular interactions
- Chemical Reactions and Mechanisms
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Reactions
- Click Chemistry and Applications
University of Manchester
2019-2025
Manchester Academic Health Science Centre
2022-2023
Liverpool John Moores University
2013-2021
University of St Andrews
2020
East Cheshire NHS Trust
2020
Liverpool Hospital
2015-2019
Parsons (United States)
2015-2019
New School
2015
AstraZeneca (United Kingdom)
2004-2014
North Staffordshire Clinical Commissioning Group
2013
Covering: the literature until April 2000
pH–rate profiles for aqueous–organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, varied substantially between the with rate maxima that over 6 orders magnitude. A mechanistic model containing five general pathways (k1–k5) has developed, together input [B]tot, KW, Ka, KaH, kinetics can be correlated a function pH (1–13) all species. Cyclopropyl vinyl acids undergo very slow protodeboronation, do 3- 4-pyridyl...
ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTMatched Molecular Pairs as a Medicinal Chemistry ToolMiniperspectiveEd Griffen‡, Andrew G. Leach*§, Graeme R. Robb§, and Daniel J. Warner∥View Author Information‡ Oncology Innovative Medicines Unit, AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.§ Cardiovascular Gastrointestinal 30S373 U.K.∥ Department of Chemistry, R&D Montreal, Quebec, H4S 1Z9, CanadaPhone: +44 1625 231853. E-mail: [email protected]Cite this:...
Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as mechanism for base-catalyzed protodeboronation arylboronic acids. However, study was limited to UV spectrophotometric analysis under acidic conditions, and aqueous association constants (Ka) were estimated. By means NMR, stopped-flow IR, quenched-flow techniques, kinetics 30 different acids has now been determined at pH > 13 in dioxane 70 °C. Included are all 20 isomers...
Experimental and theoretical data are provided for a set of 11 pericyclic reactions unsaturated hydrocarbons. Literature experimental evaluated standardized to ΔH⧧0K comparison theory. Hartree−Fock, MP2, CASSCF, CASPT2, density functional theory (B3LYP, BPW91, MPW1K, KMLYP functionals), CBS-QB3 transition-structure geometries, activation enthalpies entropies, reaction entropies these reported compared results. For enthalpies, several functionals rival CASPT2 closest agreement with...
The mechanism of the ene reaction singlet (1Δg) oxygen with simple alkenes is investigated by a combination experimental isotope effects and several levels theoretical calculations. For 2,4-dimethyl-3-isopropyl-2-pentene, olefinic carbons exhibit small nearly equal 13C 1.005−1.007, while reacting methyl groups near unity. In novel experiment, composition product analyzed to determine intramolecular in tetramethylethylene. new literature 2H are then used evaluate accuracy RHF, CASSCF(10e,...
By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in database measured properties and computing the corresponding change property, we obtain an overview effect has upon property set expectation for what will happen when is applied elsewhere. The mean indicates expected magnitude number cases which increases give probability cause to increase. Outliers indicate potential ways avoiding general trend. Comparing changes lipophilicity...
Wide-ranging exploration of analogues an ATP-competitive pyrrolopyrimidine inhibitor Akt led to the discovery clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism pharmacokinetics (DMPK) properties and, after oral dosing, pharmacodynamic knockdown phosphorylation downstream biomarkers in vivo, inhibition tumor growth a breast cancer xenograft model.
ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTBeyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding Drugs to ProteinsAdam J. T. Smith†, Xiyun Zhang†, Andrew G. Leach‡, K. N. Houk*†View Author Information Department Chemistry Biochemistry, University California, Los Angeles, California 90095, AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.* To whom correspondence should be addressed. Phone: 310-206-0515. Fax: 310-206-1843....
The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) protodeboronation ArH) a series boronic esters, encompassing eight different polyols 10 polyfluoroaryl heteroaryl moieties, have been investigated by in situ stopped-flow NMR spectroscopy (19F, 1H, 11B), pH-rate dependence, isotope entrainment, 2H KIEs, KS-DFT computations. study reveals phenomenological stability esters under basic aqueous-organic conditions to be highly nuanced. In contrast common assumption,...
Singlet oxygen, nitroso compounds and triazolinediones have similar electronic structures: they share a low lying LUMO, making them powerful electrophiles, high HOMO, orthogonal to the LUMO consisting of an antibonding combination lone paris. This bestows some nucleophilic character on these species. We describe number studies employing best levels theory currently available for systems this size demonstrate that Diels-Alder ene reactions three species are calculated show subtle changes in...
The first large scale analysis of in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) data shared across multiple major pharma has been performed. Using advanced matched molecular pair (MMPA), we combined from three pharmaceutical companies generated ADMET rules, avoiding the need to disclose full chemical structures. On top very exchange knowledge, all involved synergistically gained approximately 20% more rules transformations. There is good quantitative...
The mechanism of CF3 transfer from R3SiCF3 (R = Me, Et, iPr) to ketones and aldehydes, initiated by M+X– (<0.004 10 mol %), has been investigated analysis kinetics (variable-ratio stopped-flow NMR IR), 13C/2H KIEs, LFER, addition ligands (18-c-6, crypt-222), density functional theory calculations. kinetics, reaction orders, selectivity vary substantially with reagent (R3SiCF3) initiator (M+X–). Traces exogenous inhibitors present in the reagents, which proportion identity between batches...
The mechanism of CF2 transfer from TMSCF3 (1), mediated by TBAT (2–12 mol %) or NaI (5–20 %), has been investigated in situ/stopped-flow 19F NMR spectroscopic analysis the kinetics alkene difluorocyclopropanation and competing TFE/c-C3F6/homologous perfluoroanion generation, 13C/2H KIEs, LFERs, efficiency selectivity, effect inhibitors, density functional theory (DFT) calculations. reactions evolve with profoundly different kinetics, undergoing autoinhibition (TBAT) quasi-stochastic...
Inflammation driven by DNA sensors is now understood to be important disease pathogenesis. Here, we describe new inhibitors of sensing, primarily the inflammasome forming sensor AIM2. Biochemistry and molecular modeling has revealed 4-sulfonic calixarenes as potent AIM2 that likely work binding competitively DNA-binding HIN domain. Although less potent, these also inhibit cGAS TLR9 demonstrating a broad utility against DNA-driven inflammatory responses. The inhibited AIM2-dependent...
A bicyclic glycosyl donor is activated as an arylsulfonium ion and used to synthesise α-glycosides with high stereoselectivity.
G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements metabolic syndrome. During a program toward discovering agonists GPR119, we herein describe optimization initial lead compound, 2, into development candidate, 42. A key challenge in this work was insolubility compound. Small-molecule crystallography utilized to understand intermolecular interactions solid state resulted switch from aryl sulphone 3-cyanopyridyl...
Abstract The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl‐substituted N‐heterocycles and anilines is reported. A phosphoric acid (CPA) catalyst promotes dearomatizing aza‐Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. reaction accommodates broad range N‐heterocycles, nucleophiles, substituents on the centre, generating products in high enantioselectivity. DFT studies support facile...
The mechanism of R2BH-catalyzed hydroboration alkynes by 1,3,2-dioxaborolanes has been investigated in situ 19F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labeling (10B/2H), and density functional theory (DFT) calculations. For the Cy2BH-catalyzed 4-fluorophenylacetylene pinacolborane, resting state is anti-Markovnikov addition product ArCH = CHBCy2. Irreversible turnover-rate limiting reaction with pinacolborane (k ≈ 7 × 10-3 M-1 s-1) regenerates Cy2BH...
Chemists have many options for elucidating reaction mechanisms. Global kinetic analysis and classic transition-state probes (e.g., LFERs, Eyring) inevitably form the cornerstone of any strategy, yet their application to increasingly sophisticated synthetic methodologies often leads a wide range indistinguishable mechanistic proposals. Computational chemistry provides powerful tools narrowing field in such cases, wholly simulated mechanisms must be interpreted with great caution. Heavy-atom...