A5055231644- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Innovative Microfluidic and Catalytic Techniques Innovation
- Chemical Synthesis and Reactions
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Catalytic Cross-Coupling Reactions
- Sphingolipid Metabolism and Signaling
- Synthesis of Tetrazole Derivatives
- Synthesis and Catalytic Reactions
- Synthetic Organic Chemistry Methods
- Radical Photochemical Reactions
- Monoclonal and Polyclonal Antibodies Research
- Endoplasmic Reticulum Stress and Disease
- Molecular Sensors and Ion Detection
- Asymmetric Hydrogenation and Catalysis
- Receptor Mechanisms and Signaling
- Chemistry and Chemical Engineering
- Hormonal and reproductive studies
- Crystallography and molecular interactions
- Ion channel regulation and function
- Cyclopropane Reaction Mechanisms
- Advanced Synthetic Organic Chemistry
- Cancer Cells and Metastasis
University of Strathclyde
2016-2025
GlaxoSmithKline (United Kingdom)
2001-2020
International Union of Pure and Applied Chemistry
2008-2020
University of Würzburg
2018
Colorado State University
2018
Institut Català d'Investigació Química
2018
Universitat Rovira i Virgili
2018
University of Amsterdam
2018
Institute for Molecular Science
2018
Southeast University
2018
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis target compounds was enabled with dichlorocarbene insertion into bicyclo[1.1.0]butane system being key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained compare their counterparts, which showed isostere well tolerated positively impacted on physicochemical profile.
Abstract Elevated production of collagen-rich extracellular matrix is a hallmark cancer-associated fibroblasts (CAFs) and central driver cancer aggressiveness. Here we find that proline, highly abundant amino acid in collagen proteins, newly synthesized from glutamine CAFs to make tumour breast xenografts. PYCR1 key enzyme for proline synthesis expressed the stroma patients CAFs. Reducing levels sufficient reduce production, growth metastatic spread vivo cell proliferation vitro. Both...
Alzheimer's disease is the most common cause of dementia in elderly. Although several genetic defects have been identified patients with a family history this disease, majority cases involve individuals no known predisposition. A mutant form ubiquitin, termed Ub(+1), has selectively observed brains patients, including those nonfamilial but it unclear why Ub(+1) expression should be deleterious. Here we show that an efficient substrate for polyubiquitination vitro and transfected human cells....
A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamide.
Pd-catalysed C–C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, solvents are incompatible with drive towards more sustainable chemical synthesis. Herein, we describe scope limitations alternative to DMF derived from renewable sources (Cyrene TM ) in Sonogashira cross-coupling Cacchi-type annulations.
Cyrene was found to be an effective bio-based solvent for HATU mediated amide bond formation.
A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions aldehydes using borane-based reductants. The data generated has used to develop a guide facilitate replacement less desirable chlorinated solvents, such as DCE, from these widely synthetic processes.
The Suzuki–Miyaura (SM) cross-coupling is the most broadly utilized Pd-catalyzed C–C bond-forming reaction in chemical industry. A large proportion of SM couplings employ dipolar aprotic solvents; however, current sustainability initiatives and increasingly stringent regulations advocate use alternatives that exhibit more desirable properties. Here we describe scope utility bio-derived solvent Cyrene™ cross-couplings evaluate its suitability as a medium for this benchmark transformation from...
A catalytic amidation method has been developed, employing 2,2,2-trifluoroethanol to facilitate condensation of unactivated esters and amines, enabling the synthesis a range amide products in good excellent yields. Mechanistic studies indicate reaction proceeds through trifluoroethanol-derived active ester intermediate.
Solid-phase peptide synthesis can be monitored and optimized using non-contact computer vision methods.
A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification catalytic process are described, furnishing products in 40–100% isolated yield.
Replacement of dichloromethane as the bulk medium within chromatographic purification has been evaluated with a broad range molecules containing functionality common Medicinal Chemistry programmes. Analysis data set generated general guidelines to assist in selection alternative solvents for CH2Cl2 media these ubiquitously employed processes.
An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is reported using inexpensive (−)-riboflavin (vitamin B2) under irradiation at 402 nm. Selective energy transfer from photoexcited starting E-isomer enables geometrical isomerization. Since analogous process with Z-isomer inefficient, microscopic reversibility circumvented, thereby enabling a directional generate contra-thermodynamic product (up 99% yield, up 99:1 Z/E). Prudent...
Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range photochemical applications. Taylor–Couette (vortex, dynamically mixed) have been reported intensified and used heterogeneous systems. Our workflow has previously demonstrated development Wohl–Ziegler process scale-up in flow using plug reactor (PFR). In this work, 20 mL mixed Autichem, Ltd. prototype DART (Taylor–Couette reactor) was paired four custom Kessil PR160L 400 nm lamps. The evaluated as...
The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework the computational screening molecular descriptors guide design 24 mutants...
Knocking them into shape: The total synthesis of two reported marine natural products containing halogenated pyrano[3,2-b]pyrans (see example in blue) has led to the reassignment both structures as 2,2′-bifuranyls (red). Concomitantly an efficient route is described.
We describe the development of a sustainable ester amidation process. Base and solvent screening, combined with application Design Experiments methodology was employed to identify an optimized set reaction conditions using protocol. Utilizing these conditions, treatment range derivatives amino alcohols in presence catalytic quantity potassium phosphate deploying iso-propanol as results highly efficient generation amido-alcohol good excellent yield, accompanied mass efficiency (RME).
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report expedient, structure-guided evolution weak physiological allosteric inhibitors (bile salts) into potent competitive that do not interact with catalytic site. Functional data confirms our lead compound attenuates LPA mediated signaling in cells reduces synthesis vivo, providing promising natural product derived scaffold discovery.
The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery first series potent inhibitors mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth rapid optimization potency with maintenance ligand efficiency, while focus physicochemical properties delivered compounds excellent pharmacokinetic exposure that proof concept experiment in...
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway implicated in cell survival, migration, proliferation; thus, inhibition ATX recognized therapeutic target number diseases including fibrotic diseases, cancer, inflammation, among others. Many developed synthetic inhibitors have resembled lipid chemotype native ligand; however, small been described that deviate...